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Full text of "Effectiveness of feed additive usage of antibacterial agents in swine and poultry production [electronic resource]"

LISRARY 
UNIVERSITY OF KENTUCKY 



The Hays Report 
The Hays Report 



Digitized by the Internet Archive 

in 2010 with funding from 

NCSU Libraries 



http://www.archive.org/details/effectivenessoffOOhays 



The Hays Report 
The Hays Report 
The Hays Report 



Effectiveness of Feed Additive Usage 

of Antibacterial Agents 

in Swine and Poultry Production 



By 
Virgil W. Hays 



Edited version of Tlie Hays Report prepared for the Office of Technology 
Assessment, United States Congress. 

Published by Rachelle Laboratories, Inc., 700 He)ir\' Ford Avenue. 
Long Beach, California 9080L 



Foreword 



It was as true — as turnips is. 
It was as true — as taxes is. 
And nothing's truer tfian them. 

Charles Dickens 



Documentation of the benefits of feed additive antibiotics for swine and poultry 
production is clearly needed by producers and feed manufacturers. Perhaps more 
importantly, documentation of the benefits is needed, if feed additive antibiotic usage is 
to be sustained against the seemingly constant regulatory pressures to ban their use. The 
enclosed report presents a 30-year summary of "Effectiveness" of feed additive antibiotics 
in poultry and swine production. It is a "Commissioned Paper" prepared by Dr. Virgil W. 
Hays, University of Kentucky for the Office of Technology Assessment, Congress of the 
United States. The poultry and swine industry is truly indebted to Dr. Hays for 
accumulating, digesting, and organizing the mass of data contained in his report. The 
use of feed additive antibiotics clearly continue to be beneficial in poultry and swine 
production. 



V. C. Speer 

Professor, Animal Science 

Iowa State University 



The author received his early train- 
ing in Animal Sciences at Oklahoma 
State University and the Ph.D. in 
Animal Nutrition at Iowa State 
University. He has held research 
and teaching appointments at Iowa 
State University and University of 
Kentucky and presently is Professor 
of Animal Nutrition and Chairman 
of the Department of Animal Sci- 
ences at the University of Kentucky. 

Professor Hays has extensively 
studied the effects of antibacterial 
agents on performance of animals, 
development and transfer of anti- 
biotic resistance and tissue clearance 
of antibacterial agents. He has writ- 
ten extensively on the biological 
effectiveness of antibacterial agents 
and factors affecting their responses. 



PREFACE iii 

FOREWORD V 

ABOUT THE AUTHOR vii 

I. INTRODUCTION 1 

II. MODE OF ACTION 3 

A. Metabolic Effect 3 

B. Nutrient Sparing Effect 3 

C. Disease Control Effect 10 

III. CONTINUED EFFECTIVENESS 21 

IV. EFFECTIVENESS OF ANTI BACTERIAL AGENTS 

IN SWINE FEEDING PROGRAMS 3 1 

V. EFFECTIVENESS OF ANTIBACTERIAL AGENTS 
IN FEEDING PROGRAMS FOR GROWING 

CHICKS AND LAYER HENS 41 

VI. EFFECTIVENESS OF ANTIBACTERIAL AGENTS 

IN FEEDING PROGRAMS FOR TURKEYS 47 

VII. EFFECTS OF ANTIBIOTICS ON MORTALITY AND 

MORBIDITY 50 

VIII. SUMMARY 51 

IX. RESEARCH NEEDS 52 

BIBLIOGRAPHY 53 



I. Introduction 

Antibiotic feed supplements have been extensively used in every major livestock and 
poultry producing country for more than 27 years. In the United States alone, tiie non- 
medical sales of antibiotics averaged 1.05 million kg annually between 1963 and 1972 
(see figure 1 ). 



PRICE AND SALES VOLUME OF ANTIBIOTICS 
FOR NONMEDICAL USES 



Price 

S/kg. 




1300 
1100 

900 

1000 
ks. 

700 Sold 

500 
300 
100 



<-Year 



U.S. Tariff Comm. 1951 - 1972 
Figure 1. Average price and total sales of antibiotics for nonmedical uses, 1951 
to 1972(536). 

In addition, substantial quantities of arsenicals and nitrofuran drugs are used. The wide 
acceptance of antimicrobial agents is attributable to the known benefits of increased 
growth rate, improved feed conversion and reduced mortality and morbidity due to 
clinical or subclinical infections. 

Antibacterial agents commonly used in swine and poultry production as dietary additives 
include bacitracins, chlortetracycline, erythromycin, neomycin, oxytetracyciine, oleando- 
mycin, penicillin, streptomycin, tylosin, arsenicals and nitrofurans. Recently bambermy- 
cins and virginiamycin have been added to the approved list. Among those presently used, 
some are more effective as growth promoters tlian others. Other antibiotics Iiave sliown 
promise experimentally as effective additives; several which are not approved as feed ad- 
ditives are used as therapeutic agents. 



The total number of antibiotics approved for use in livestock and poultry production, 
either as feed additives or for therapeutic usage, total about 14. This is a substantial 
number; however, Raper (428) reported that some 300 antibiotics had been described and 
partially evaluated by 1952; since then many others have been discovered and evaluated. 
Therefore, only a small percentage of antibiotics available has been found to have major 
application; the majority are unsuitable for one or more reasons, including low activity, 
toxicity to the host animal, resultant tissue residues, etc. Some may be quite effective 
but offer no particular biological advantage over those presently used; thus their develop- 
ment on an industrial level cannot be justified. Though the quantity produced and sold 
varies from year to year, about 40% of the antibiotics sold in the U.S. is for nonmedical 
uses, mainly as feed additives (see figure 2). 

TOTAL AND NON -MEDICAL SALES OF ANTIBIOTICS 



S? 2.0 




70 (-Year 



U.S. Tariff Comm., 1949-73 
Figure 2. Sales of antibiotics for medical and nonmedical uses, 1949 to 1973 (536). 

It is widely recognized that antibiotics effective in improving the performance of animals 
have one thing in common: the suppression or inhibition of the growth of certain micro- 
organisms. Their chemical compositions and bacterial spectra vary widely. Some of the 
effective antibiotics are readilv absorbed into the vascular systenijothers are barely ab- 
sorbed. The chemical compositions, bacterial spectra and absorption and excretion pat- 
terns of these products are clearly associated with their bactericidal and bacteriostatic 
properties and effectiveness against specific systemic infections; however, these character- 
istics are less readily associated with effectiveness as a routine growth promoter. 



II. Mode of Action 

For the growth-promoting activity of antibiotics, at least three modes of action have been 
postulated, each with varying degrees of support: (a) The metabolic effect: The antibiotics 
directly affect the rate or pattern of the metabolic processes; (b) The nutrient-sparing 
effect : The antibiotics may reduce the dietary requirement for certain nutrients by stim- 
ulating the growth of desirable organisms which synthesize vitamins or amino acids, by 
depressing the organisms which compete with the host animal for nutrients, by increasing 
the availability of nutrients via chelation mechanisms, or by improving the absorptive ca- 
pacity of the intestinal tract; (c) The disease control effect: The suppression of organisms 
causing clinical or subclinical disease, by inhibition of multiplication of organisms that 
produce toxins, or by limiting their capacity to produce toxins which reduce performance 
but result in no obvious symptoms of disease. 

A. Metabolic Effect 

The data which support the metabolic effect theory also tend to support a disease- 
control effect, as the rate of metabolism may be influenced by systemic infections, 
digestive upsets or absorption of microbially-produced toxins from the gastroin- 
testinal tract. Metabolic reactions are influenced by antibiotics: Braude and Johnson 
(65) reported that the feeding of chlortetracychne affected water and nitrogen 
excretion and suggested that it may influence the metabolic rate of pigs; Brody 
et ah (73), using rat liver homogentates, found that tetracyclines inliibited fatty 
acid oxidation by the mitochondria. Weinberg (571) also showed that, in bacteria, 
phosphorylation and oxidation reactions requiring magnesium ions were inhibited 
by tetracyclines; and, Hash et al_. (207) demonstrated that tetracyclines inliibited 
protein synthesis. 

Numerous reports illustrate that antibiotics have metabolic implications, and that 
bacteriostatic or bactericidal properties are associated with metabolic effects. How- 
ever, in view of the nature of the animal responses, the normal tissue levels of the 
antibiotics when added to the diet at growth promoting levels and the levels neces- 
sary to mediate such biochemical responses, the metabolic effects cannot account 
for the growth promotion in animals fed diets supplemented with moderate levels 
of antibiotics. Furthermore, a direct metabolic effect should not vary greatly with 
the environmental conditions as discussed in the subsequent section on disease 
control effect. A direct metabolic effect could be consistent with variations discuss- 
ed in the nutrient sparing section as nutrient levels at the site of metabolic reac- 
tions could modify rate and extent of metabolic reactions. 

B. Nutrient Sparing Effect 

The nutrient-sparing effect has considerable research support. It is well recognized 
that certain intestinal organisms synthesize vitamins and amino acids which are 
essential and that other bacteria require and compete with the host animal for 
these essential dietary nutrients. 

Moore et al. (359) reported that streptomycin stimulated the growth or permitted 
rapid growth of some yeasts; Anderson et al. (8) ifound that feeding diets containing 



penicillin increased the numbers of intestinal coliforms other than Escherichia coli . 
Such organisms synthesize nutrients that are dietary essentials; if a diet is deficient 
in a specific nutrient, this deficiency could be partially corrected by microbial 
synthesis and the specific nutrient subsequently made available for absorption by 
the host through digestion of the microorganism or by other means of release of the 
nutrient from the microorganism. 

Other researchers report a depression in growth of organisms that are considered 
competitive with the host animals for dietary needs. March and Biely (315) indi- 
cated that the bacteria most affected by chlortetracycline were the lactobacilli. 
Anderson et al. (9) and Johansson and Sarles (258) also reported that antibiotics 
caused a reduction in the numbers of lactobacilli; Anderson et al_. (9) reported that 
penicillin decreased the number of enterococci in the cecum of the chick. The 
lactobacilli require amino acids in relatively proportionally similar amounts as chicks 
and pigs; studies have shown that levels and sources of proteins which support 
maximum growth in pigs are also near optimum for the multiplication of lactobacilli 
in the intestinal tract (Kellogg et a[. 273a). Hence the bacteria can compete with 
their host for essential amino acids not present or deficient in the diet. Though 
these bacteria may later be digested, the site of digestion may be past the site of 
optimal absorption. It has also been observed that those antibiotics most effective 
in reducing the number of these organisms in the intestinal tract, thus reducing com- 
petition for nutrients, are also the most effective as routine growth promoters 
(Kellogg et ah 272). A reduction in populations of organisms which compete with 
the host animal for the dietary essential nutrients may be beneficial, especially if 
the levels of certain essential nutrients are critically low. Such mechanism of action 
could partially explain the unusually marked responses reported for some experi- 
ments in the early 1950's, when optimum levels of many of the essential amino 
acids and vitamins were unknown. 

Another type of nutrient sparing effect could be the improved utilization, parti- 
cularly improved absorption, of the limited quantities of nutrients available to the 
host animal. Catron et ah (99) reported an increased rate of glucose absorption in 
animals fed rations fortified with antibiotics, thus providing evidence for the im- 
proved nutrient utilization by improvement of the absorptive capacity of the in- 
testinal tract. Coates (110) demonstrated that the gut wall was thinner in chicks 
fed rations containing an antibiotic than the intestinal wall of chicks fed diets not 
containing antibiotics. Rusoff et al. (433b) and Braude et al_. (64) observed similar 
effects in calves and pigs, respectively. Coates also noted that feeding chicks the in- 
testinal contents of infected chicks resulted in a thickening of the intestinal wall. 
Similar effects of antibiotics on the thickness of the intestinal wall have been re- 
ported by others (Coates et al.. Ill; Gordon, 184, 185a; Gordon et a[., 185b; 
Hill et_al., 236; and Taylor and Harrington, 522). The thinner intestinal wall implies 
a potential for improved absorption (Taylor, 521) and is assumed to be a result of 
the inhibition of the organisms which produce toxins or of the production of toxins 
which damage intestinal tissue. Improved utilization of nutrients due to a healthier 
intestinal wall actually could be classed as reduction in subclinical disease or 
inhibition of toxin production. 

Catron et al_(98), Burnside et ah (83) and Beacom (30, 3 1) reported research which 



suggested that the level of protein required by pigs for maximum performance was 
less in the presence of dietary supplements of antibiotics. Tables 1 and 2 summarize 
the response of pigs and chicks, respectively, to varying protein levels in the pre- 
sence or absence of antibiotics and show that maximum gains may be obtained at a 
slightly lower level of protein if antibiotics are present in the diet or expressed dif- 
ferently; rate of gain is depressed more by low protein in the absence than in the 
presence of the antibiotic. 

TABLE 1 

EFFECT OF CHLORTETRACYCLINE ON WEIGHT GAINS OF PIGS FED 
PROTEIN AT FOUR LEVELS^ 







Average 


Daily Gain (g) 


Feed Efficiency" 


Protein 




Fed Chlor- 




Fed CWor- 


Level Fed i 


(%) 


Control 


tetracycline 


Control 


tetracycline 


20-17-14C 




690 


760 


3.90 


3.54 


18-15-12 




708 


754 


3.83 


3.60 


16-13-10 




740 


760 


3.72 


3.55 


14-11-8 




681 


754 


3.74 


3.59 



^CatrOne^al^. (98). 
■^Units of feed per unit of gain. 

^Percent protein in the diet for the weight periods initial to 68, 34 to 68 and 68 to 
91 kg. body weight, respectively. 

TABLE 2 

EFFECT OF ANTIBIOTICS ON THE RESPONSE OF CHICKS TO VARYING 

PROTEIN LEVELS^ 



Protein 




Weight, 


g 




Feed/Gair 


1 


Level 


Controls 


Antibiotic 


Improvement 


Controls 


Antibiotic 


Improvement 


% 


g 


g 




% 








% 


16 


977 


1055 




8.0 


3.32 


3.03 




8.7 


18 


1058 


1161 




9.7 


3.06 


2.82 




7.8 


20 


1133 


1171 




3.4 


2.97 


2.93 




1.3 


22 


1097 


1153 




5.1 


3.22 


3.05 




5.3 


24 


1123 


1149 




2.3 


3.24 


3.07 




5.2 



^Summary of 4 experiments. West and Hill (574). 



The eflect of protein level on response is more obvious in the chick data in Table 
2. The optimum level of protein for chicks is about 20%. At or above that level, 



chick weights were improved by 2.3 to 5.1%. Below that level, antibiotics im- 
proved chick weights by 8.0 to 9.7%. Note similar effects on feed/gain. 

Not only is there an interaction of antibiotics and level of protein (provided the 
levels of protein tested include a definite sub-optimum level) but also there is an 
interaction of antibiotics and the quality (amino acid balance) of protein. For 
young calves and pigs, milk proteins are definitely superior to vegetable proteins 
because the former are more readily digested and have superior amino acid balance. 
An e.xample of the antibiotic x protein quality interaction is provided by Hogue 
et a[. (240); the amount of milk in the diet of young dairy calves influenced tlieir 
response to antibiotics. Though the growth rate of the calves was higher on the 
higher levels of milk, the response to chlortetracycline was greater (11.3%) versus 
5.1%) on the poorer quality (low milk) diet (Table 3). 



TABLE 3 

EFFECT OF CHLORTETRACYCLINE ON GROWTH OF CALVES FED MILK 

AT TWO LEVELS^ 



Daily/Gain 



Level of Milk Fed 



Average (g) 



Improvement (%) 



Low 

Control 

Fed Chlortetracycline 
High 

Control 

Fed Chlortetracycline 



481 
534 

527 
554 



11.3 



5.1 



^Hogue et al_. (240). 



Such diet x antibiotic interactions are reported for other species as well. From a 
comprehensive summary of the effects of antibiotics on the performance of beef 
cattle, Burroughs et al. (84a) also noted that animals on diets which resulted in 
less rapid and efficient gains (lower quality or lower in available nutrients) showed 
a greater percentage response to chlortetracycline (Table 4). 



TABLE 4 

EFFECT OF CHLORTETRACYCLFNE ON WEIGHT GAINS OF BEEF CATTLE 
FED HIGHER AND LOWER GAINING DIETS^ 



Daily Gain 



Feed/Gain" 



Diet and No. 
Comparisons 



Average Improve- Average Improve- 
(kg) ment (%) ment (%) 



Higher gaining diets (34 comparisons) 

Control 1.057 

Fed Chlortetracycline 1 . 1 03 

Lower gaining diets (3 1 comparisons) 

Control .645 

Fed Chlortetracycline .681 



4.3 



5.6 



10.34 
9.96 

12.31 
11.45 



3.7 



7.0 



^Burroughs et a].. (84a). 
"Units of feed per unit of gain. 

Lucas (304), Braude et al_. (66, 67), Stokstad (502), Burnside e^al_. (81 ) and others 
presented evidence of an association between diet and antibiotic response. This re- 
lationship can be seen in the change in response to antibiotics over years in Table 5. 



TABLE 5 

RESPONSE OF PIGS TO ANTIBIOTICS DURING THE STARTER STAGE 
(PIGS WEIGHING LESS THAN 35 POUNDS AT START OF TEST) 







Number^ 


Wt. 


Ib.^ 


ADG 


,lb.c 






Feed/G; 


inc 




Exp 


Reps. 


Pigs 


1 


F 


- 


+ 


%Imp. 


- 


+ 


^'. Imp. 


Tetracyclines'^ 


59 


234 


1654 


17 


53 


.83 


.92 


10.84 


2.24 


2.10 


6.25 


Bacitracin^ 


11 


54 


228 


15 


43 


.72 


.79 


9.72 


2.15 


2.08 


3.26 


Tylosin' 


21 


124 


878 


18 


51 


.81 


.93 


14.81 


2.32 


2.18 


6.03 


Penicillin- 
























Streptomycin 


40 


95 


545 


25 


73 


1. 01 1 


.16 


14.85 


2.56 


2.37 


7.42 


Virginiamycin'^ 


23 


90 


629 


23 


68 


1. 00 1 


.1 1 


11.00 


2.39 


2.27 


5.02 


Bambermycins' 


5 


24 


128 


11 


30 


.53 


.53 


0.00 


2.03 


2.05 


-0.99 


Penicillia' 


7 


14 


57 


13 


40 


.74 


.81 


9.45 


2.19 


2.00 


8.68 


Chlortetracycline- 
























Sulfamethazine- 
























Penicillin*^ 


78 


302 


2507 


18 


52 


.78 


.96 


23.07 


2.22 


2.03 


8.56 


Chlortetracycline- 

Sulfathiazole- 

PenicUlin'^ 


9 


31 


292 


22 


61 


.93 


.11 


19.35 


2.40 


2.20 


8.33 



continued 
7 







Number^ 


Wt. 


Jb.h 


ADG, Ib>' 






Feed/Gain'^ 




Exp 


Reps 


Pigs 


I 


F 


— 


+ 


%lmp. 


— 


+ 


'"( Imp. 


Tvlosin- 
























Sulfamethazine' 


17 


76 


482 


20 


51 


.85 


1.00 


17.65 


2.07 


1.93 


6.76 


Carbadox"! 


82 


292 


2195 


21 


60 


.97 


1.15 


18.56 


2.43 


1 T) 


8.64 


Lincomycin'^ 


3 


8 


52 


27 


110 


1.35 


1.50 


11.11 


2.51 


2.32 


7.57 


Nitrofurans° 


23 


66 


376 


23 


83 


1.00 


1.08 


8.00 


2.57 


2.51 


2.33 


Sums 


378 


1410 


10,023 


















Weighted avg. 








19 


57 


.87 


1.01 


16.09 


2.32 


2.16 


6.90 


Tetracyclines: 
























1950-1956 


6 


16 


104 


15 


50 


.92 


1.00 


8.70 


2.20 


2.08 


5.45 


1957-1966 


38 


128 


863 


15 


50 


.77 


.86 


11.69 


2.27 


2.09 


7.93 


1967-1977 


15 


90 


687 


24 


61 


.94 


1.04 


10.63 


2.18 


2.13 


2.29 



^Number of experiments and number of replications (pens) and pigs per treatment. 

"Initial and final weight, lb. 

'^Average daily gain and feed/gain for pigs fed diets without (-) and with (+) antibiotics 

^Chlortetracycline and oxytetracycline. References: 22,23,36,55,79,98, 102, 107, 108, 127, 129, 
147, 159, 216, 218, 220a, 242, 257, 259, 277, 294, 313, 426, 470, 494. 

^References: 28, 108a, 123, 129,257,294. 

fReferences: 32,33, 129, 147,247,257,277,284,298,398,434,494,538. 

gPenicillin-Streptomycin. References: 34,35,36,55,68, 108, 147,255,257,350,398,408,427, 
494,540,543.553. 

•^References: 3, 125b, 129, 147,257,285,343,347,348,395,396,424,434. 

iReferences: 277,494. 

JReferences: 494. 

^Chlortetracycline, Sulfamethazine or Sulfathiazole, Penicillin. References: 3, 4, 103, 104, 108, 147, 
157a, 157b, 159, 161, 200, 201, 202, 203, 217, 219, 238, 259, 277, 280, 284, 313, 333, 334, 341, 
375, 386, 390, 398, 455, 494, 529b, 532, 546, 550, 551, 552, 589. 

Ijylosin- Sulfamethazine. References: 108, 247, 333, 334, 335, 341, 386, 436, 494, 529b. 

"^References: 3,4, 126, 147, 157a, 198, 201, 219, 341, 369, 385, 386, 390, 398, 435, 529b, 531, 532, 
546,549,552. 

"References: 3, 199. 

^References: 4, 20, 23, 24, 27, 108, 238, 425, 55 1 , 552, 549. 



In the 1950"s most of the research with young pigs involved diets containing rela- 
tively high levels of milk products, in more recent years, much of the research 
effort has been devoted to improving performance on diets without milk, since milk 
is considered too expensive to use extensively in pig starters. Thus, while no change 
or a decrease in the response to antibiotics can be expected a higher level of response 
in the starter stage since 1957 than prior to 1957 is seen. The response to antibio- 
tics is generally greater if the antibiotics are included in an inadequate diet. This 
response suggests an improved utilization of nutrients at critical or suboptimal 
levels and can be ascribed to nutrient synthesis by intestinal organisms, reduced 
competition from bacteria for critical nutrients or improved absorption. 

Though there is substantial evidence that antibiotics will markedly enhance the 
performance of animals fed a diet low in protein or inadequate in other nutrients, 
there is evidence that the effect on nutrient utUization is indirect. Meade and 
Forbes (332), Wallace et al. (565) and Bush et_ al_. (84b) presented evidence sug- 
gesting that enhancement in growth was accompanied by an increase in food intake; 
and though total nitrogen, calcium or other nutrients retained was greater, the 
percentages retained by the two groups of animals (those fed antibiotics and those 
not fed antibiotics) were similar. The increased feed intake accompanying re- 
sponse to antibiotics may provide evidence that the response is not a result of a 
direct effect on nutrient absorption or utOization; however, such evidence does not 
detract from the practical benefits of antibiotics. The improved feed intake may 
simply be a result of improved health resulting in improved growth rate and appetite, 
thus leading to improved efficiency. Environmental conditions existing in most 
balance studies (extreme cleanliness, one animal per metabolism crate, controlled 
temperature, etc.) are not conducive to dramatic antibiotic responses. Studies per- 
formed in more practical conditions in which feed intake was limited to a standard 
level, as practiced in Europe, have shown that responses to antibiotics occur even 
though feed intake is held constant. Data summarized by Melliere (336) illustrated 
that pigs fed at a restricted level responded to tylosin (Table 6). 

TABLE 6 
RESPONSE TO TYLOSIN IN PIGS FED A RESTRICTED AMOUNT OF 

FEED PER DAY^'l^ 



Item 


Controls 


Plus Tylosin 
22-44 ppni 


Improvement 


No. replications 


93 


86 




Pigs per treatment 


876 


839 




Avg. daily feed intake, g 


1958 


1938 




Avg. daily gain, g 


597 


625 


4.69 


Feed/gain 


3.31 


3.13 


5.44 



=^Melliere. 336. 

"Results of trials on commercial farms in Germany, England. Holland and Italy. 



In the United States growing pigs, chicks and turkeys are normally allowed ad 
lihitum access to food. 

Tlie increased response to antibiotics in tlie presence of nutritional stresses is of 
major economic significance in the production of meat, milk and eggs, since it is 
often economically desirable or pragmatically convenient to feed nutrient sources 
or levels which will not promote maximum rate of gain. In livestock and poultry 
feeding programs, antibiotics may partially bridge the gap between optimum and 
economically practical diets. More specifically, protein supplies may be too expen- 
sive (as in the example of milk in pig starter diets) to permit the feeding of optimum 
levels. Feed quality may also vary depending on growing, harvesting or storage 
conditions. Such variations are beyond the control of livestock producers and can- 
not be entirely corrected by diet formulation. 

Disease Control Effect 

Thougli there is extensive evidence of nutritive and antibiotic response relationships, 
such effects appear secondary to the disease-control effect. Numerous studies sup- 
port the conclusion that the major benefits derived from antibiotics as routine feed 
additives result from the suppression or control of subclinical or nonspecific dis- 
eases. Early in the history of antibiotics as supplements to animal feeds, it was 
noted that the degree of response to antibiotics was inversely related to the general 
well-being of the experimental animals. Speer el ai. (497) observed that healthy, 
well-nourished pigs did not respond to antibiotic supplements when housed in 
carefully cleaned and disinfected pens which had not been previously used. These 
findings have been confirmed by other research with other species (Catron et_dL, 
100; Coates et al., 1 12 and Hill et al., 234). 

Studies involving both clean and contaminated environments illustrated that the 
response was greater in contaminated or previously used environments. Bowland 
(56) presented results of pig tests involving a new and an old barn. His data, sum- 
marized in Table 7, show that antibiotics resulted in a 14.3% increase in growth 
rate of pigs housed in the old barn; in the new barn, antibiotics resulted in only a 
7.5% increase in growth rate. 



TABLE 7 
EFFECT OF CHLORTETRACYCLINE ON WEIGHT GAINS OF PIGS 
IN DIFFERENT ENVIRONMENTS^ 



Environment and 


Daily Gain 


Feed EtTic 


iency'' 


Ciilortetracycline 
Fed 


Average Improve- 
(g) ment (7f) 


Average 


Improve- 
ment (%) 


New barn 








Control 


604 


4.15 




Chlortetracycline 
(9 g/ton) 


649 7.5 


3.92 


5.5 


Old barn 








Control 


604 


4.21 




Chlortetracycline 
(9 g/ton) 


690 14.2 


3.78 


10.2 



^Bowland (56). 

"Units of feed per unit of gain. 10 



Similar differences were noted for improvements in feed conversion in the new and 
old barns. Bird et a].. (48) presented similar results with chicks. The response of 
chicks to chlortetracycline in a new environment was 12.6% improvement in gains 
during four weeks, as compared to 18.2% for chicks from the same hatch that were 
reared in the previously used environment (Table 8). Coates et al. (1 12) reported 
similar observations (Table 8). 



TABLE 8 

RESPONSE OF CHICKS TO CHLORTETRACYCLINE (CTC) AND 
PENICILLIN IN NEW AND PREVIOUSLY USED ENVIRONMENT 



Environment 



Treatment 



4 wk. Wt. 

(g) 



Improvement 

(%) 



Bird,etai.,48 
New house 

Previously used house 

Coates, etal., 112^ 
Greenford Lab. 

Reading Lab. 



Control 


254 




CTC, lOppm 


286 


12.6 


Control 


176 




CTC, lOppm 


208 


18.2 


Control 


184 




Penicillin 


187 


1.6 


Control 


155 




Penicillin 


192 


23.9 



^Reading Lab. had been previously used to house chicks but the Greenford Lab. had not. 



11 



In a previously used environment, penicillin increased gains by 23.9%; gains were 
improved by only 1.6% in the unit not previously used. 

Wachholz and Heidenreich (538) provided additional evidence that the cleanliness 
or previous use of the environment affected the magnitude of the response to anti- 
biotics (Table 9). 



TABLE 9 

RESPONSE TO TYLOSIN BY PIGS HOUSED IN TWO 
ENVIRONMENTS - NEW BARN VS. DIRT LOTS^ 



Environment 




New House 






Dirt Lots*^ 




TylosinC 





+ 


Improve- 
ment (%) 





+ 


Improve- 
ment (%) 


ADG, kg. 














Starter 


.55 


.63 


14.6 


.42 


.50 


19.0 


Grower 


.84 


.82 


2.4 


.58 


.68 


17.2 


Finisher 


.95 


.99 


4.2 


.73 


.80 


9.6 


Feed /gain 














Starter 


2.48 


2.29 


7.7 


2.74 


2.53 


7.6 


Grower 


2.53 


2.56 


4.2 


3.19 


2.94 


8.0 


Finisher 


3.15 


3.15 


0.3 


3.70 


3.52 


4.9 



^Wacliholz and Heidenreich (538). 

"Area had been used several years for rearing pigs. 

'^l 10, 44 and 1 Img/kg., respectively for starter, grower and finisher diets. 



They tested the growth promoting effects of tylosin in a new barn and in a dirt lot 
facility which had been used for pigs for several years. The increased rate of gain 
from supplementing the diet with tylosin averaged 2.4 to 14.6% in the new barn as 
compared with 9.6 to 19% in the dirt lot facility, a less desirable environment. Ob- 
viously new buildings cannot be provided for each batch of chicks or pigs, but such 
data illustrate the need for improved sanitary practices. 

Hays and Speer (216) conducted two field tests comparing the effectiveness of dif- 
ferent levels of spiramycin (Table 10). 



TABLE 10 

EFFECT OF SPIRAMYCIN AND TETRACYCLINES 
ON WEIGHT GAINS OF PIGS FED IN TWO ENVIRONMENTS^ 





Total Gain 


Feed Efficiency 


Level of Spiramycin 


Average 


Improvement 


Average 


Improvement 


Fed 


kg. 


(%) 




(%) 


First environment^' " 










No antibiotic 


8.13 




1.90 




12.5 g/ton 


9.62 


18.3 


1.84 


3.2 


25 g/ton 


10.44 


28.4 


1.64 


13.7 


50 g/ton 


10.81 


33.0 


1.70 


10.5 


Tetracycline^ 


10.71 


31.7 


1.78 


6.3 


Second environment ' § 










No antibiotic 


4.81 




2.89 




12.5 g/ton 


6.13 


27.4 


2.40 


17.0 


25 g/ton 


7.99 


66.1 


L95 


32.5 


50 g/ton 


8.40 


74.6 


1.83 


36.7 


Tetracycline^ 


7.35 


52.8 


2.03 


29.8 



^HaysandSpeer(2I6). 
"Unit of feed per unit of gain. 

'^Building thorouglily cleaned and disinfected before test, occupied only by pigs in test. 
64 pigs fed at each level, averaging 26.3 days of age and 5.63 kg. body weiglit, initially. 

®50 g/ton of chlortetracycline or oxytetracycline in first and second environments, 
respectively. 

Building not thorouglily cleaned before test and contained older pigs before and during 
test. 

^59 pigs fed at each level, averaging 31.8 days of age and 5.69 kg. body weight, initially. 



In one test, the building was emptied, thoroughly cleaned and disinfected before 
st-^rting the test, and only those pigs involved occupied the buOding during the test. 
The building used in the other test contained older pigs preceding and during the 
test, and neither the building nor the individual pens were thoroughly cleaned or 
disinfected before the test. In the cleaner environment, spiramycin (50 g/ton of 
diet) resulted in a 33% improvement in gains and a 10.5% improvement in feed ef- 
ficiency; in the uncleaned building, the addition of the same level of antibiofic to the 
diet resulted in a 75%o increase in growth rate and a 37% improvement in feed con- 
version. Similar responses to cWortetracycline (50 g/ton) and to oxytetracycline 
(50 g/ton) were noted. 



13 



Lower levels of spiramycin resulted in lower response. Though other variables, such 
as climatic conditions and breeding of animals, may have influenced the perfor- 
mance, the relative contamination of the buildings obviously had an important 
bearing on response to antibiotics. The buildup of a nonspecific infection in 
buildings continuously used to house animals can depress performance of animals 
without resulting in obvious symptoms of a disease problem. This is the kind of 
problem for which routine feeding of antibiotics is useful and therapeutic use is not 
indicated. 

Scott (449) presented an excellent example of the buildup of the growth depressing 
effect of non-specific infections in a chick starting facility. The performance of suc- 
cessive hatches of chicks of similar breeding and fed similar diets was poorer than 
that of previous hatches (Table 1 1). 



TABLE 11 
EFFECT OF A "NON-SPECIFIC INFECTION" ON CHICK GROWTH^ 

Hatch No. Avg. Gain 0-7 Days Relative Gain 

(%) 
100.0 
96.6 
93.9 
90.7 
96.8 
94.6 
92.5 
91.0 
89.4 
79.7 



85.3 
59.3 

86.4 
78.1 
64.0 

^Adapted from Scott, 449. 



14 









(g) 


1 






44.2 


2 






42.7 


3 






41.5 


4 






40.1 


5 






42.8 


6 






41.8 


7 






40.9 


8 






40.2 


9 






39.5 


10 






35.2 


Depopulation 


and 


fumigation 




11 






37.7 


12 






26.2 


Depopulation and fumigation 




13 






38.2 


14 






34.5 


15 






28.3 



Emptying the facility, cleaning it thoroughly and fumigating it resulted in some 
improvement in performance. However, even this did not result in a growth rate 
of chicks approaching the level of performance of the first hatch. These are the 
kinds of problems which feed additive usage of antibiotics help to control. Some 
critics of antibiotic usage have suggested that the only need for antibiotics results 
from housing pigs and chicks in filthy overcrowded houses. Such statements are 
greatly exaggerated and suggest that the individuals are not acquainted with practi- 
cal livestock and pouhry production. Even in the new house illustrations above, 
there were responses to antibiotics. Furthermore, the most uninformed should re- 
cognize that new facilities or complete isolation cannot be afforded for each far- 
rowing of pigs or hatch of chicks. 

Tlie challenge experiments of Miyat and Gossett (353) further demonstrated the pro- 
phylactic effects of antibiotics in controlling specific diseases (Table 1 2). 

TABLE 12 

EFFECT OF FEEDING TYLOSIN ON EXPERIMENTALLY INDUCED 
HEMORRHAGIC DYSENTERY IN PIGS^ 



Amount of Tylos 


in Fed 
In Feed 


No. Pigs 


at 


Average 


Weight (k 


g) 




Start of 


End of 


Feed 


In Water 


g/ton 


Trial 


Trial 


Initial 


Final 


Efficiency" 


TRIAL 1 




















24 


12 


16.66 


37.82 


20.6 


250 mg/gal9 


40d 


23 


23 


16.57 


57.52 


2.85 


250 mg/gaF 





23 


20 


16.66 


47.31 


3.84 





lOOe 


24 


23 


16.57 


62.97 


2.82 


TRIAL 2 




















23 


13 


35.96 


59.02 




250 mg/gaic 


40d 


21 


19 


35.32 


64.65 


4.20 


250 mg/gaF 





22 


20 


36.37 


63.97 


4.90 





100^ 


23 


18 


35.90 


67.28 


5.86 



^Miyat and Gossett (353). 

Units of feed per unit of gain. 
^Antibiotic included in water for 6 to 8 days before infection and for 4 or 5 days after 

infection. 

"40 g/ton of feed after water treatment 

^100 g/ton of feed for 2 days before and for 33 or 15 days after infection, followed by 
40 g/ton. 



15 



Treatment with tylosin was effective in controlling hemorrhagic dysentery, hut 
treatment followed hy prophylactic administration of the antihiotic was more ef- 
fective in restoring performance to normal. These data illustrate the marked im- 
provement in performance resulting from antihiotic supplements in severely high 
and, in this case, specific disease conditions. Similar ohservations have been re- 
ported on naturally occurring outbreaks of hemorrhagic dysentery (Gossett and 
Miyat, 186). 

Braude e^'d[. (67) summarized a large number of experiments and concluded that 
the relative improvement in growth rate resulting from supplementing the diets with 
antibiotics was inversely related to the growth rate of the control animals (Table 1 3). 



TABLE 13 
RELATIONSHIP BETWEEN GROWTH RATE OF CONTROL ANIMALS AND 
ANIMALS FED ANTIBIOTICS^ 





Daily Gain 


in Weight (g) 


Response to 
Antibiotic: 




Control 


Antibiotic-Fed 


No. of Tests 


Animals 


Animals 


Improvement (%) 


4 


94 


245 


161 


1 


136 


227 


67 


r2 


182 


336 


85 


13 


227 


340 


50 


16 


272 


449 


65 


31 


318 


481 


51 


12 


363 


499 


38 


18 


409 


563 


38 


16 


454 


572 


26 


36 


499 


572 


15 


32 


545 


627 


15 


39 


590 


636 


8 


48 


636 


713 


12 


20 


681 


735 


8 


22 


726 


790 


9 


1 


772 


881 


14 



^Adapted from Braude eta[. (67). 



Similar experiments, involving the antibiotic combination of penicillin and strepto- 
mycin and conducted about ten years after the studies by Braude et al_. are sum- 
marized and presented in Table 14. 



TABLE 14 

RELATIONSHIP BETWEEN GROWTH RATE OF CONTROL PIGS 
AND PIGS FED A COMBINATION OF PENICILLIN AND STREPTOMYCIN^ 



Daily Gain In 


Improvement Over Controls By 
Pigs Fed Antibiotics 


Weight of No. of 
Controls (g) Comparisons 


Gain in 
Weiglit (%) 






Feed 
Efficiency (%) 


91 to 182 2 


22.0 






8.2 


182 to 272 3 


27.0 






4.5 


272 to 363 4 


20.4 






5.6 


363 to 454 7 


16.1 






11.1 


454 to 545 9 


12.3 






6.4 


545 to 636 9 


9.4 






1.9 


636 to 726 20 


5.6 






4.7 


726+ 7 


3.8 






1.8 


Total 61 










Average Improvement, % 


10.7 






5.1 



^Data summarized from agricultural experiment station reports, 1960 to 1967 (212a). 



Of 61 comparisons included in the summary, 56 showed a positive response in feed 
conversion, with average improvements of 10.7% and 5.1% for rate of gain and feed 
efficiency, respectively. 

As mentioned earlier, the observation that degree of response is associated with 
degree of contamination has led to the suggestion that antibiotics are being used as 
a substitute for good housekeeping and sanitation procedures. There are practical 
and economic limits which can be made by livestock producers in sanitation 
procedures. Experiment stations, which usually employ husbandry and sanitation 
practices beyond the practical limits of producers, do, nonetheless, note responses 
to antibiotics of substantial magnitude. 

The data used to estimate the economic benefits from the use of antibiotics are for 
the most part based on experiments conducted at experiment stations. Most of the 



17 



data used in estimating benefits to poultry is based on performance of chicl<s in 
batteries. Experiment station researchers employ management and sanitation pro- 
cedures that are difficult, or nearly impossible, and certainly often impractical for 
the producer. For example, many of the tests involve only healthy pigs at the be- 
ginning; however, the farmer must rear all of liis pigs. The exaggerated response 
to antibiotics by unthrifty (runt) pigs is illustrated by a number of experiments, 
some of which are summarized in Table 15. 



TABLE 15. 
VALUE OF CHLORTETRACYCLINE FOR UNTHRIFTY PIGS^ 

As Percent of Controls 



Exp. ADG F/G 

1 203 79 

2 184 79 

3 315 63 

4 215 76 

5 121 87 

6 151 86 

7 186 78 

8 161 86 

9 149 83 

10 173 69 

11 300 71 



Avg. 196 77 



^Braude et d. (67). 



Researchers normally cull out this quality of pigs prior to starting the experiments. 
Note that antibiotics resulted in a near doubling of tlie growth rates and improved 
feed efficiency by an average of 77%. These studies are included in the upper part 
of Tables 13 and 14. Sainsbury (439) also presented an excellent example of the 
difference in response of normal healthy pigs and those he classed as "bad doers" 
or what we frequently term as "runt" or "unthrifty" pigs. Antibiotic supplements 



to the diet of the noimal pigs resuhed in a 10% improvement in rate of gain; anti- 
biotic supplements to the "bad doers" resulted in a 30% improvement in gains. 
Thus, if unselected pigs are used (as the producer must), a greater response to 
antibiotics is expectable than if only healthy pigs are selected. 

Also, researchers usually clean the facility well and the facility may be idle between 
groups of pigs or chicks. This practice should result in a lesser response to antibio- 
tics as illustrated in Table 10. It is difficult or nearly impossible to thorouglily 
clean and sanitize many swine facilities. 

Another procedure commonly followed in many experiments which undoubtedly 
reduces the stress on animals and hence reduces the expected response to antibio- 
tics is the practice of using only a few animals per pen. In fact, some of the antibio- 
tic studies involve single pigs per pen; most involve only 4 to 6 animals per pen. It 
is obvious that this is not a practical management procedure. It is common practice 
to have 75 to 100 or more pigs per pen. Many chick and turkey experiments in- 
volve 10 or fewer birds per pen and often in wire floored batteries; in practical 
production, hundreds may be housed per pen. 

Melliere et a].. (338) summarized 69 swine experiments conducted under research 
station and farm conditions and verifies that the average response is greater in the 
farm situation. Their data are reported in more detail by Natz (374) and sum- 
marized in Table 16. 

TABLE 16. 

EFFECT OF TYLOSIN ON GROWTH RATE 
AND FEED CONVERSION OF FINISHING PIGS^ 





Trials 




Treatment 




Experimental Unit 


Control 


Tylosin 10-20 


Improvement 


Average daily gain 


No. 




g/day 


% 


Research type I*' 


32 


790 


803 


1.7 


Research type 2^ 


22 


763 


790 


3.6 


Field tests^ 


24 


713 


754 


5.7 



Avg. 



755 



783 



3.7 



Feed/gain 
Research type I'' 
Research type 2'^' ^ 
Field tests^ 

Avg. 



32 
16 
24 



3.36 
3.64 
3.84 

3.61 



feed/gain 



3.35 
3.52 
3.66 

3.51 



0.3 

3.3 

4.7 



continued 



19 



^Meniere (338) and Natz (374). 

Closed herds, confinement houses thoroughly cleaned prior to test. 
'^Herd status and cleaning procedures not defined. 

Practical production units. 

^Feed/gain data available on only 16 of the 22 experiments for which rate of gain data 
were available. 



The average response for rate of gain and feed/gain was 5.7 and 4.7, respectively in 
field trials as compared with 3.6 and 3.3 for University Experiment Station tests. 
In experiments carried out in faciUties in which extreme care was taken to maximize 
sanitary conditions, the response was 1 .7 and 0.3% improvement in gain and feed/ 
gain, respectively. Table 17 also presents a summary of differences in response to 
antibiotics in practical and experiment station environments, summarized from the 
observations included in Table 5. 



TABLE 17 
RESPONSE TO ANTIBACTERIALS (STARTER PIGS)^ 



% Improvement 



Location A.D.G. F/G 

32 Field tests 28.4 14.5 

128 Exp. Sta. tests 16.9 7.0 



^Summarized from data included in Table 5 and based on 
experiments involving 12,000 pigs. The antibacterials tested 
include tetracycline, tetracyclines in combination with penicillin 
and sulfamethazine, carbadox and the combination of tylosin 
and sulfamethazine. 



Note that in field conditions the response to antibacterial agents is nearly double 
that observed for experiment station conditions. Thus, if the economic benefits 
are calculated from the use of antibiotics on data from experiments in the field, 
rather than from experiment station data, such benefits would greatly exceed the 
533 million dollar estimate of Gilliam and Martin (181) for economic returns to use 
of antibiotics in swine production. 



It has been suggested that there is no need for feed additive usage of antibiotics if 
one has a Specific-Pathogen-Free (SPF) or Minimal Disease (MD) herd. SPF and MD 
are terms used in the U.S. and Great Britain, respectively, to designate animals that 
are free of mycoplasma pneumonia, atropliic rhmitis and possibly other diseases 
that are spread by direct pig to pig contact. Any reduction in disease should lower 
the response to antibiotics. However, there are many experiments which illustrate 
that SPF pigs respond to antibiotics. Much of the data available has been sum- 
marized by Hays (211), and indicates that there is little difference in responses to 
antibiotics by SPF and non-SPF pigs used in experiment station research. Sainsbury 
(439) also reported that MD pigs fed antibiotic supplemented diets grew 8% faster 
than their respective controls as compared with a 10% improvement for conven- 
tional pigs supplemented with antibiotics. Every practical method should be 
utihzed to reduce the morbidity and mortality from disease; however, at present 
there are no methods available that would contraindicate the need for feed ad- 
ditives. The wise use of antibiotics is not a substitute for but complements good 
husbandry, sanitation and disease control practices. 

III. Continued Effectiveness 

The extensive use of antibiotics as feed additives has elicited concern about potential 
harmful effects due to the development of resistant strains of organisms in the host ani- 
mal or due to resistant organisms or allergic reactions in the consumer of the meat, milk 
or eggs from animals continuously fed antibiotics. Concern should exist with the appHca- 
tion of any new drug either as a feed additive or a medicament; but, after 27 years of 
usage of some of these drugs, fear should have changed to rational thinking leading to ade- 
quate evaluation of the potential harmful effects as contrasted with the proven health and 
economic benefits. 

After more than 27 years of extensive use of antibiotics in animal feeds, discussions still 
deal with "potential" public heahh hazards, as did a presentation 16 years ago (Goldberg, 
183). Significantly, it is difficult to cite a single human health problem that can be at- 
tributed to the consumption of meat from animals fed antibiotics or that can be associated 
with direct or indirect contact with animals fed antibiotics. 

It has been well established that continuous exposure of enteric organisms to an anti- 
biotic permits the development of strains of organisms with greater tolerance for or com- 
plete resistance to that antibiotic. This is more readily demonstrated in laboratory tests 
(in vitro) with pure cultures than it is with the complex microflora which exists in the 
environment or in the gastrointestinal tract of domestic animals. However, an increase in 
multiple and transferrable drug resistance has been observed in naturally occurring enteric 
organisms from the use of antibiotics as feed additives (Smith et al., 485, and others). 

The evidence that resistant organisms in animals compromise treatment of diseases in 
man or animals is indirect and difficult to evaluate. For those persons concerned only 
with disease treatment, the idealistic decision is to strictly limit the use of any drug to 



21 



treatment of a patient now or a "potential" patient in the future. For those who are 
concerned with a healthy population and a plentiful food supply, which involves 
both disease protection and efficient food production, the decisions are more complicated. 
A thorough evaluation of the human health implications of any biologically active drug 
is essential. When there are benefits, that is when there is some biological activity, there 
are likely to be some risks involved. A more thorougli discussion of the risks or potential 
risks of feed additive usage is covered in other papers. 

It has been suggested that antibiotics are losing their effectiveness and that ever higlier 
levels are being required to give the typical antibiotic response. The general explanation 
for this is that the problem organisms are developing or have developed resistance to the 
antibiotics. It is recognized today that 40 to 50 g/ton of a broad spectrum antibiotic is 
normally required to approach a maximum response, whereas the generally recommended 
level in the 1950's was 10 to 20 g/ton. However, the data of Catron et al. (100) illustrate 
that, since antibiotics were first used, the recommended feeding level has not necessarily 
been the level which would elicit maximum response. Even though a response was obtained 
with 10 to 20 g/ton (Table 18), maximum gain was approached at 40 g/ton, and maxi- 
mum feed efficiency was realized only at 80 g/ton, the higliest level tested. 



TABLE 18. 

EFFECT OF CHLORTETRACYCLINE FED AT DIFFERENT LEVELS 
ON PERFORMANCE OF GROWING-FINISHING SWINE^ 



Level of Chlortetracycline 
(g/ton) 


Average Daily 
Gain (g) 


Feed Consumed 
Per Day (g) 


Feed Efficiency^ 





654 


2343 


3.69 


10 


722 


2443 


3.49 


20 


726 


2479 


3.50 


40 


758 


2588 


3.44 


80 


763 


2561 


3.36 



^Catronetal. (100). 
Feed required per unit gain. 



Braude, et al.. (67) reported in 1953 that more than 20 g/ton of tetracycline or penicillin 
was required for maximum response. Excluding experiments involving inadequate diets 



22 



or runt pigs, the percentage responses to tetracycline were 15.2 and 18.6 and to penicillin 
were 9.1 and 13.1 for below and above 20 g/ton, respectively. These observations were 
based on 125 tetracycline experiments and 45 penicillin experiments. 

The levels selected for practical use are not necessarily the levels that will elicit maximum 
response. The growth response increases with increasing levels of antibiotics, up to 250 
g/ton or more in some cases. The rate of increase in growth response decreases, however, 
as the level of antibiotic increases; thus, the level selected in practice is usually a com- 
promise based on the cost-benefit ratio. 

Improved methods of producing antibiotics and competition among producers have 
resulted in a decline in the price of the commonly used antibiotics, which allows consider- 
ation of the use of higher levels. Figure 1 presents price data for all antibiotics combined 
and Table 19 presents the specific price liistories of penicillin, streptomycin and tetracy- 
clines. 

TABLE 19. 

APPROXIMATE PRICE PER KILOGRAM OF FEED-GRADE ANTIBIOTICS 
FOR THE SPECIFIED YEARS, 1950-1975 

Year 

1950 
1955 
1960 
1965 
1970 
1975 



The prices of feed-grade penicDlin and streptomycin in 1975 were only 10 to 15% of the 
1950 price and tetracycHnes were only about 20% as expensive as in 1950. These reduc- 
tions in antibiotic prices were accompanied by increases in most other production costs. 
The evidence available suggests that the decrease in cost of antibiotics per gram and the 
increase in other production costs have been the primary reasons for higher levels being 
recommended and used rather than any decline in effectiveness. The higlier levels were 
more effective from the beginning; but, with the natural biological phenomena of a de- 
creasing rate of increase with an increasing level, the practical optimum level changes 
with cost changes, not only of the antibiotics, but other production costs and in addition 
change with the market prices received for pigs. Prices of certain antibiotics have 
increased within the past five years. These have essentially attained basic commodity 



23 



Penicilhn 


Streptomycin 


Tetracyclines 


$200 


$200 


$120 


50 


55 


100 


22 


30 


80 


20 


20 


60 


24 


28 


30 


26 


29 


22 



status (patent protection is gone for the older ones) and prices will respond to ingredient, 
labor, transportation and other routine production costs. Removal of the older antibio- 
tics from use in livestock production will increase cost of production, as it will force the 
use of drugs that still are covered by patent protection in addition to removing some of 
the most effective in terms of improving rate and efficiency of gain. 

Certainly, there are tests in which little or no response is observed to a recommended 
level of an antibiotic. This situation is not peculiar to the present. Similar observations 
have been reported since the early use of antibiotics as dietary supplements. Speeret ah 
(497) reported that 10 to 20 g of chlortetracycline per ton of diet did not improve the 
performance of pigs in one test and suggested that the low disease level could be the 
reason for lack of improvement. 

Teague et a[. (523) reviewed the antibiotic studies conducted at the Ohio Station between 
1950 and 1963. Variations were noted in the response from year to year, but there was 
no consistent decline in antibiotic response. A similar study of the swine data from the 
Iowa Station, 1950 - 1959, suggests that less response to antibiotics existed (Figure 3) 
during 1953-1956. 





+15 


- •^ 




-^ 














+9.6 




+10 


- 


• ' 


\ 
















% 


+ 5 


- 




\ 


\ 




-"^ 




^ 




(Av) 


IMPROVEMENT 





- 






V 














IN GAINS 


- 5 
-10 


- 






^^ 














NO. PIGS 


757 


630 


418 


48 16 


66 


92 


376 


72 


48 


2523 


YEAR 


1950 


1951 


1952 


19 53 1954 


1955 


1956 


1957 


1958 


1959 


Total 


COMPARISONS 


35 


26 


12 


1 3 


4 


3 


20 


3 


2 


109 




-2 5 


- 




















% 





- 








/ 


/^ 


\, 




; 




IMPROVEMENT 


+2.5 
+5.0 




^•- 






^ 




\ 


V / 


/ 


+4.5 


IN F/G 


-"^ 






+7.5 


_•/ 














V 




(Av) 



INITIAL Wt. (lb) RANGE: 16-55 (Av. 29), FINAL Wt. 44-110 (Av. 77) 
ANTIBIOTICS: OXYTET, P, B, P-B, P-S, OLEANDO, CHLORTET — B-P. STREPT 



Figure 3. Response of growing pigs to antibiotics (V. C. Speer, Animal Science 
Department, Iowa Agric. and Home Econ. Exp. Sta.) 



A critical evaluation of the experiments conducted during those years shows that few were 
performed and usually involved individually fed pigs in experiments designed to study the 
effects of antibiotics on protein or vitamin utilization. The disease stress on the animals was 
thus minimized as most of the animals were individually penned in metabolism cages. 

Peo (397) summarized the long-term effects of antibiotic feeding to swine at the Nebraska 
Station and concluded that, after more than ten years of extensive use of antibiotics, a re- 
sponse was still being observed. His observations are particularly relevant, since, in that 
period of time, the Nebraska researchers had changed to a "specific pathogen-free"herd 
and had strived to keep disease conditions at a minimum. 

Hvidsten and Homb (250) reported the results of 9 consecutive experiments on one farm 
in which oxytetracycline and chlortetracycline were tested at low or high levels. Tlie 
antibiotic-fed pigs gained 5% faster on the average for the 9 trials and the average im- 
provement for the 9th trial was 5.3%. The lowest response to antibiotics was observed in 
the 4th trial and the liigliest in the 5th trial, suggesting that the variations in results was 
largely a result of normal variation associated with small experiments, and not a reflection 
of a changing response to antibiotics. 

To evaluate the continued effectiveness of tetracycline and the combination of tetracy- 
cline, penicilHn and sulfamethazine, the data in Table 5 were statistically analyzed. The 
differences between control and treated groups were liigWy significant (P<.01 ) for average 
daily gain and feed required per pound of gain, for both the tetracycline experiments and 
the experiments involving the antibiotic combination. For the tetracycline experiments 
the predicted difference was 0.10 lb/day increase in rate of gain and a reduction of 0.12 
lb. of feed per pound of gain as a result of having the antibiotic in the diet. There was no 
evidence of a reduced effect with successive years of use. The predicted improvements in 
rate of gain and feed conversion were 1 1.3% and 4.6%, respectively, as compared with the 
observed values of 10.8% and 6.2%. The predicted differences were adjusted to a common 
initial weight (17.4 lb.) and equal time on experiment (40.4 days). 

For the experiments involving the combination of antibiotics, there was evidence of a 
year by treatment interaction. A plot of the data showed an improvement with time in 
rate of gain for the controls followed by a leveling or dropping off, with little or no 
change in the performance of the treated group. The difference between controls and the 
treated group was highly significant (P<.01). There was no evidence of a year by treat- 
ment interaction for feed/gain ratios with a constant difference of 0.17 lb. less feed per 
pound of gain for the treated group. The predicted improvement in feed conversion was 
7.6% as compared with the observed average of 8.5% in Table 5. The predicted values are 
adjusted to equal initial weights (18.4 lb.) and to equal time on experiment (36.2 days). 

Tlie statistical analysis of each of these sets of data supports the conclusion that tetracy- 
cline or the combination of tetracycline, penicilHn and sulfamethazine is still effective in 
improving performance, with little or no evidence of a decline in effectiveness with time. 

Similar questions have been raised about the continued effectiveness in poultry. Bird 
(46) summarized data from 1951 to 1968 on birds taken from hatching to broiler weights 



25 



and concluded that the trends did not indicate a decrease in effectiveness. Table 20 pre- 
sents a series of trials from 1964 to 1976 in which penicillin was used as a standard in 
screening tests (Kiser, 273b). 



TABLE 20 
SUMMARY OF CHICK RESPONSE TO PENICILLIN^ 





No. of 
Expts.l' 


Birds Fed 
Basal Diet 

Gain (g) F/G 


Bird 
Penicillin 

Gain (g) 


5 Fed 
n Diet ^ 

F/G 


'~( Improvement over Basal 


Year 


Gain + S.E.M. 


F/G±S.E.M. 


1964 


11 


250 


1.76 


294 


1.56 


17.5 + 1.71 


1 1.3 ± 1.66 


1965 


23 


289 


1.64 


324 


1.52 


12.1 +0.87 


6.9 ±0.58 


1966 


43 


291 


1.63 


330 


1.50 


13.4 + 0.68 


7.8 ±0.48 


1967 


23 


267 


1.69 


311 


1.52 


16.6+ l.OI 


9.5 ±0.70 


1968 


38 


262 


1.64 


301 


1.53 


15.0+ 1.03 


6.9 ±0.61 


1969 


39 


266 


1.60 


310 


1.45 


16.4 + 0.86 


8.2 ±0.54 


1970 


30 


271 


1.58 


310 


1.45 


14.3 ±0.88 


8.1 ±0.47 


I97I 


12 


316 


1.54 


357 


1.43 


13.0 + 2.19 


7.4± 1.15 


1972 


24 


193 


1.47 


211 


1.37 


9.3 + 1.36 


6.8 ±0.76 


1973 


24 


183 


1.49 


203 


1.39 


10.8 ±0.72 


6.5 + 0.47 


1974 


44 


189 


1.45 


207 


1.36 


9.7 ±0.68 


6.1 ±0.48 


1975 


44 


188 


1.47 


202 


1.40 


7.6 ± 0.37 


5.3 ±0.22 


1976 


36 


190 


1.47 


206 


1.39 


8.5 ±0.71 


5.3 ±0.56 


a Kiser, 


273b. 















Each experiment contained 2 replicates of 10 birds each (5 males, 5 females). Trial lengths were 
20 days for 1964 to 1967, 19 days for 1968 to 1971 and 13 days for 1972 to date. 

''Penicillin was present at 180 g/ton of diet. 



After 12 years of continuous testing in the same laboratory, penicillin still results in sub- 
stantial improvements in performance. The percentage increase is lower in recent years, 
but the overall performance of the birds has improved, particularly feed efficiency. It 
should be noted that the length of test period has changed from 20 to 13 days (see foot- 
note b). If one corrects for normal day-old weights, the rate of gain is equal to or superior 
in the first 13 days in 1976 as it was for the first 20 days in 1964 The change is greater 
for the controls than for the penicillin treated, another indicatic-" ihat the reauction in 
percentage improvement due to antibiotics is a result of improved performance of con- 
trols rather than a regression of the penicillin treated birds. Waibel et al. (556) titled a 



26 



No. Trials 


Average Response 
% of Controls 


31 




112.3 


29 




110.2 


46 




108.5 


15 




110.2 



paper "Disappearance of a Growth Response in Chick to Dietary Antibiotics in an Old 
Environment." Heth and Bird (223) summarized the data from the same laboratory used 
by Waibel et a[. but over a longer period of time and found the average responses to be 
similar for 1950-53 as compared with 1956-59 (Table 21). 



TABLE 21 

GROWTH RESPONSE OF CHICKS TO ANTIBIOTICS 
FROM 1950 to 1961^ 

Antibiotic Period 

Tetracycline, 10-35 ppm 
1950-1953 
1955-1960 

Penicillin, 4-30 ppm 
1950-1953 
1956-1959 

Zinc Bacitracin, 10-35 ppm 

1956-1959 16 105.9 

Zinc Bacitracin, 100 ppm 

1956-1959 115.2 

^Heth and Bird, 223. 



Heth and Bird (223) and Libby and Schaible (296) reported that in a given environment 
the growth response of chicks to an antibiotic may be reduced but noted that the general 
level of growth increased during the time period, leading the authors to conclude that 
antibiotics had reduced the number of harmful organisms in the environment so that the 
control chicks grew better, rather than the antibiotic fed birds regressing to the control 
level. 

Tlie improved performance of controls with time should not all be attributed to a reduc- 
tion of suppressive organisms; genetic and dietary progress has also been made. The im- 
provement in diets should also result in a decrease in percentage response to antibiotics 
as discussed in the section on mode of action. Other than the instance cited above of 
using penicillin as a control drug in screening tests (Table 20), the continuous use of a 
single antibiotic has not been critically evaluated, as it is not general practice for a live- 



27 



stock producer or a researcher to feed antibiotics throughout the animal's life cycle or to 
use the same antibiotic year after year. However, numerous experiments have been 
carried out that shed some light on whether the more commonly used antibiotics are con- 
tinuing to improve the performance of animals. Elliot and Johnson (I 57b) conducted 
several experiments on a single commercial swine farm over a period of six years. A sum- 
mary of their evaluation of a combination of chlortetracycline, penicillin and sulfametha- 
zine is presented in Table 22. 



TABLE 22 

EFFECT OF FEEDING ANTIBIOTICS ON WEIGHT GAINS OF SWINE, 
IN TESTS ON A SINGLE COMMERCIAL FARM, 1960-1965^''' 





Avera 


ige Daily Gain 


Feed Efficiency'^ 


Date 




-f 






+ 




Experiment 
Started 


Controls 


Anti- 
biotic 


Improve- 
ment 


Controls 


Anti- 
biotic 


Improve- 
ment 




(g) 


(g) 


(%) 






(%) 


Dec. 1960 


263 


413 


57 


2.13 


2.11 


1.0 


Mar. 1961 


222 


395 


78 


2.08 


1.85 


11.1 


Apr. 1962 


186 


359 


93 


2.15 


1.81 


15.8 


May 1964 


191 


336 


76 


2.99 


2.18 


27.1 


Sept. 1964 


200 


322 


61 


2.71 


2.36 


12.9 


Oct. 1965 


250 


331 


32 


2.77 


2.28 


17.7 



^Elliott and Johnson (157b). 

I- 

Antibiotic: 100 g. of clilortetracycline, 100 g. of sulfamethazine and 50 g. of penicillin 
per ton of diet for pigs 3 to 9 weeks of age. 

^ Units of feed per unit of gain. 



This svnne producer had routinely fed diets containing chlortetracycline, but not penicillin 
and sulfamethazine, during the entire period. Other antibiotics may have been fed inter- 
mittently for short periods. The average performance and the response within any one 
year varied probably as a result of the environmental conditions, including stresses, exist- 
ing at the time the experiment was conducted. But, after six years of testing, tlie com- 
bination of chlortetracycline, sulfamethazine and penicillin resulted in a 32% improve- 
ment in rate of gain and an 18% improvement in feed efficiency. 



28 



Hays (211b) conducted an experiment on the same commercial swine farm that Elliot 
and Johnson used. The results of that experiment are presented in Table 23. 



TABLE 23 



EFFECT OF FEEDING ANTIBIOTICS AT HIGH LEVELS 



ON WEIGHT GAINS OF YOUNG PIGS 



a, b 



Level of 


Daily 


Gain 


Feed/Gain'- 


Feeding 
Antibiotic (g/ton) 


Average 
(g) 


Improve- 
ment (%) 


Average 


Improve- 
ment (%) 


Control 


318 




2.30 




Penicillin-streptomycin" 250 


454 


43 


1.98 


13.9 


Clilortetracycline-sulfamethazine -peni- 250 


427 


34 


1.94 


15.7 


Penicillin-streptomycin'^ '^'"'" 100 


395 


24 


2.02 


12.2 


Clilortetracycline 100 


396 


25 


2.14 


7.0 



^V. W. Hays (unpublished data, experiment 6443, Iowa Agr. Home Econ. Exp. Sta., 21 lb). 

Average initial weight of pigs, 8.67 kg.; 4 pens of 10 pigs each per treatment, 34 days on test. 
Pigs nursed sows prior to going on experiment. 

''Unit of feed per unit of gain. 

1:3 ratio of procaine peniciUin to streptomycin. 

^100 g. of clilortetracycline, 100 g. of sulfamethazine and 50 g. of penicillin per ton of diet. 



The response to the antibiotic combination was similar for the two studies: an improve- 
ment of 32% and 34% in growth rate and an improvement of 16% and 18% in feed con- 
version for the two tests conducted in 1965 (Tables 22 and 23). Table 23 also shows a 7% 
improvement in feed conversion and a 25% improvement in rate of gain resulting from 
the addition of chlortetracycline, thougli it had been used extensively on the farm for at 
least five years. Tlie combination of penicillin and streptomycin resulted in similar im- 
provements in performance. 

The results of similar tests using tylosin from 1959 to 1966 are summarized in Table 24 
(Jordan, 262b). 



29 



TABLE 24 

EFFECT OF FEEDING TYLOSIN FOR A PROLONGED PERIOD 
ON WEIGHT GAINS OF PIGS^ 





Experiments 




Average Daily G 


ain 






Feed/Gain 




Years 


Controls 
(g) 


Plus, 
Tylosin'' I: 
(g) 


mprovement 

(%) 


Controls 


Plus , 
Tylosin'' 


Improvement 


19591960 


3 


445 


490 




10 


1.98 


1.92 


3.0 


196I-I962 


1 


454 


499 




10 


2.21 


2.12 


4.1 


1963-1964 


1 


254 


286 




13 


1.90 


1.80 


5.3 


1965-1966 


3 


277 


327 




18 


2.20 


2.04 


7.3 


1959- 1960 


I 


409 


490 




20 


2.33 


2.15 


7.7 


1965-1966 


1 


281 


304 




8 


2.32 


2.05 


11.6 



^Jordan {262b). 
100 g. of tylosin per ton of diet, except for last 2 lines in which the level of tylosin was 40g/ton. 



The rates of gain and feed conversion by the animals in the later experiments were less 
than in the earlier years, which Jordan attributes to change in the management program 
and use of a more simpHfied diet which contained little or no milk products. The per- 
centage of response is actually greater in 1965-1966 as compared with 1959-1962, in 
keeping with the previous examples of an increased response for animals under nutritional 
stress. 

Hays and Baker (2 12b) conducted an experiment specifically to test the response to chlor- 
tetracycline in a confinement svvane unit in which the antibiotic had been continuously 
used for more than three years. The unit housed 650 to 700 pigs continuously for the 
three-year period, which would allow ample time for resistance problems to develop. 
Though the resistance patterns of the intestinal organisms were not determined we can 
state with confidence, from our present knowledge of antibiotic resistance, that the in- 
testinal coliforms were solidly resistant to tetracyclines and that resistance was a multiple 
and transferable type. As illustrated in Table 25, chlortetracycline (50 g/ton) resulted in 
a 10.2% improvement in growth rate and a 1.0% improvement in feed efficiency. 



30 



TABLE 25 

EFFECTS OF CHLORTETRACYCLINE ON WEIGHT GAINS OF PIGS 
AFTER CONTINUED USE=^' ^ 

Average 
Daily Improve- Feed Improve- 

Group Gain (g) ment (%) Efficiency^ ment (%) 

Control (36 pigs) 577 2.97 

Fed chlortetracycline 

(35 pigs) 636 10.2 2.94 1.0 

^Hays and Baker (212b). 

Chlortetracycline had been used continuously in the building for 3 years before the test, 
and pigs had received chlortetracycline before the start of the experiment. 

^ Units of feed per unit of gain. 

^^50 g. of chlortetracycline per ton of diet. 



A thorough evaluation of available data suggests that those antibiotics found to be effec- 
tive as feed additives in the 1950's are still effective in the 1970's. The magnitude of the 
response varies from experiment to experiment; caution must be used in basing con- 
clusions on one experiment. Such a cautionary statement should not be necessary for a 
researcher in biology, but normal biological variation may not be well understood by 
those not experienced in conducting animal experiments and in the principles of bio- 
statistics. Such variability may not be appreciated by those researchers who are ex- 
perienced only in in vitro work in which greater control of the environment can be ac- 
complished. 

IV. Effectiveness of Antibacterial Agents in Swine Feeding Programs 

Tables 5, 26 and 27 present a summarization of data from journal articles, field day re- 
ports and unpublished data secured through private communications from research 
workers. 



31 



TABLE 26 

RESPONSE Ob' PIGS TO ANTIBIOTICS DURING THE GROWER-DEVELOPER STAGE 
(35 TO 1 25 POLINDS BODY WEIGHT) 







Niimbei 


.a 


Wt. 

1 


.lb." 
F 




ADG, lb 


c 


Feed/Gain'' 


Antibiotic 


Exp. 


Rep. 


Pigs 


- 


+ 


" Imp. 


- 


+ 


''r Imp. 


Tetracyclines" 


120 


325 


1851 


35 


11 1 


1.28 


1.42 


10.93 


3.09 


2.97 


3.88 


Bacitracin^ 


22 


51 


328 


39 


109 


1.37 


1.44 


5.10 


2.80 


2.73 


2.50 


Tylosin 


27 


71 


968 


39 


110 


1.28 


1.42 


10.94 


2.86 


2.74 


4.20 


Virgiiiiamycin^ 


52 


142 


985 


38 


114 


1.31 


1.45 


10.69 


2.88 


2.69 


6.60 


Banibermycins" 


8 


45 


372 


44 


112 


1.63 


1.67 


2.45 


2.56 


2.53 


1.17 


Clilortctracycline-suiralhia/oie- 
penicillin' 


3 


4 


33 


44 


159 


1.35 


1.58 


17.03 


2.91 


2.82 


3.09 


Clilortetracycline-sLilfanielha/inc- 
penicillin' 


24 


58 


493 


41 


91 


1.25 


1.47 


17.60 


2.63 


2.45 


6.84 


Tylosin-sulfamethazine J 


5 


13 


156 


45 


110 


1.56 


1.64 


5.12 


2.79 


2.73 


2.15 


Carbadox ^ 


15 


63 


463 


34 


90 


1.19 


1.37 


15.13 


2.75 


2,56 


6.91 


SUMS 


276 


772 


5649 


















WEIGHTED A VG. 








37 


109 


1.31 


1.45 


10.68 


2.91 


2.78 


4.47 


Tetracyclines: 
























1950-1956 


51 


146 


802 


36 


104 


1.21 


1.42 


17.36 


3.19 


2.99 


6.27 


1957-1966 


51 


122 


686 


35 


1 15 


1 3i 


1.41 


6.02 


3.07 


3.01 


1.95 


1967-1977 


18 


57 


363 


35 


121 


1.34 


1.42 


5.97 


2.89 


2.82 


2.42 


Chlortetracycline-sulfametliazine- 


■penicillin: 






















1957-1966 


I) 


24 


167 


39 


82 


1.15 


1.41 


22.61 


2.75 


2.54 


7.64 


1967-1977 


18 


38 


359 


42 


108 


1.32 


1.52 


15.15 


2.62 


2.46 


6.11 



^Number of experiments and number of replica lions (pens) and pigs per treatment. 

Initial and final weight, lb. 

^■Average daily gain and feed/gain for pigs fed diets withoiii (-) or with ( + ) antibiotics. 

'^Chlorietracycline and oxytetracycline. References: 24, 26, 27, 28, 30, 34, 37, 38, 45.50,57,72,80,82,83.97, 130, 
147, 154, 191, 205, 219, 220a, 221, 222, 246, 255, 256, 294, 302, 306, 343, 347, 349, 350, 375, 398, 409, 423, 425, 
427. 494, 497, 498, 525, 530, 540, 543, 547, 548, 553, 563, 579, 93, 102, 1 26a, 227. 

•^References: 34, 55, 72, 120, 130, 255, 256, 279, 347, 356,408,427, 494, 524, 5 79. 

'References: 34. 35. 191, 220b, 265, 279, 280, 335, 343. 347, 375. 380. 398.409,427.434. 553. 579. 

^References: 26,28,34,35, 153b, 191 . 2 14. 262a, 285. 302. 343, 345, 347. 380, 425,434. 

'^References: 335,356,547. 

' Chlortetracycline, penicillin and sulfamethazine or sulfathiazolc. References: 2, 4, 103. 220b. 278. 356. 357. 375. 380, 
385, 408, 529b, 589, 344, 457. 

J Tylosin-sulfamethazine. References: 344,408. 



References: 4. 298. 375, 380, 38 1 . 494. 529b, 213. 



TABLE 27 



RESPONSE OF PIGS TO ANTIBIOTICS DURING THE GROWING-FINISHING STAGE 
(TESTS CONTINUED TO MARKET WEIGHT) 







Number 


a 


\Vt. 

1 


, Ib.'^ 
F 


ADG, lb 


c 


1 


Feed/Gain 




Exp. 


Reps. 


Pigs 


- 


+ 


aimp. 


- 


+ 


'■' I nip. 


Penicillin-streptomycin " 


34 


74 


557 


49 


194 


1.55 


1.61 


3.87 


3.44 


3.38 


1.74 


Bacitracin^ 


29 


106 


491 


52 


206 


1.60 


1.64 


2.50 


3.37 


3.28 


2.67 


Tetracycline' 


108 


348 


2325 


40 


199 


1.52 


1.62 


6.58 


3.53 


3.44 


2.55 


Tylosin^ 


26 


105 


758 


53 


201 


1.51 


1.58 


4.64 


3.41 


3.36 


1.47 


Bambermycins*^ 


12 


52 


461 


59 


207 


1 .59 


1.62 


1.89 


3.42 


3.38 


1.17 


Virginiamycin' 


21 


86 


514 


43 


206 


1.57 


1 .66 


5.73 


3.38 


3.27 


3.25 


Arsenicals) 


42 


158 


490 


32 


134 


1.35 


1.36 


0.74 


2.96 


2.94 


0.68 


Nitrofiirans 


7 


14 


70 


52 


201 


1.41 


1.43 


1.42 


3.39 


3.37 


0.58 


SUMS 


279 


943 


5666 


















WEIGHTED AVG. 








44 


190 


1.51 


1.57 


3.97 


3.37 


3.30 


2.08 


Penicillin-Streptomycin: 
























1950-1956 


6 


9 


54 


30 


185 


1.53 


1.68 


9.80 


3.55 


3.28 


7.61 


1957-1966 


16 


32 


258 


48 


188 


1.56 


1.62 


3.85 


3.44 


3.42 


0.58 


1967-1977 


12 


33 


245 


61 


207 


1.54 


1.57 


1.95 


3.39 


3.38 


0.29 


Tetracyclines: 
























1950-1956 


44 


163 


869 


39 


199 


1.49 


1 .63 


9.40 


3.74 


3.57 


4.55 


1957-1966 


34 


78 


764 


37 


195 


1.53 


1.62 


5.88 


3.50 


3.46 


1.14 


1967-1977 


30 


107 


692 


44 


204 


1.54 


1.61 


4.55 


3.25 


3.22 


0.92 


Bacitracin: 
























1950-1956 


5 


6 


40 


37 


199 


1.49 


1.50 


0.67 


3.70 


3.60 


2.70 


1957-1966 


1 


2 


12 


40 


184 


1.56 


1.54 


-1.28 


3.55 


3.26 


8.17 


1967-1977 


23 


98 


439 


56 


208 


1.63 


1.68 


3.06 


3.29 


3.21 


2.44 



''Number ofexperiments and number of replications (pens) and pigs per treatment. 

'''Initial (I) and final (F) weights, lb. 

''Average daily gain and feed/gain for pigs fed diets without (-) or with ( + ) antibiotics. 

^Combination of penicillin and streptomycin. References: 55. 137. 147. 180. 221, 254. 256, 265. 280. 398. 408. 
543,553. 



^References: 69, 117. 120, 129.256,279,356,385,398,408,494,524.589. 

'"Chlortetracvcline and o.xytetracycline. Retm-nces: 21 . 26. 28, 31 , 39, 51, 55, 71. 72, 80. 83,98, 100, 129, 173, 
187, 191, 196, 202, 205, 215, 220a, 221, 222, 239, 246,255,291,294,302.343,375,398.402,409,437,494, 
541, 542, 543, 547, 548, 553, 564, 565, 579, 590, 594, 70, 75, 77, 121. 

gReferences: 129, 221, 265, 280, 291, 335, 343, 375, 398, 408,409, 529b, 553, 5 79, 589. 

''References: 335, 341 , 356, 375. 408, 494, 547. 

' References: 26,28, 129, 191.214,285,302,343. 

J Includes arsanilic acid and 3-nitro-4-hvdroxv phenvlarsanic acid and experiments for all stages of production. 
References: 24,37,69,78, 108a, 127, 204, 210, 294', 375, 398, 425, 494, 175. 

•^References: 25, 391. 



33 



Efforts were made to omit data from studies in which nutrient deficiencies were involved. 
For example, some of the earlier studies with antibiotics were designed to evaluate the 
feed grade sources of antibiotics as contributors of both the antibiotic and "animal 
protein factor" or vitamin Bi2- Studies that involved feed ingredients such as raw 
soybeans, which exaggerate the antibiotic response, were also excluded. Those studies in 
which the animals were fed individudly in metabolism cages were excluded as these 
represent an abnormal situation in which little or no response to the antibiotic can or 
should be expected. In addition, the data are primarily limited to experiments conducted 
in the United States. Since management and housing practices as well as diets and feeding 
management differ from country to country and these affect the response to antibiotics, 
it is deemed advisable to emphasize U.S. data. 

The average responses to the individual antibacterial agents or commonly used combina- 
tions are presented in the upper part of the tables; for some, the results are reported by year 
periods (1950-56, 1957-66 and 1967-77) in the bottom part of the tables. The three 
tables cover the three stages of production for which it is a common practice to make 
ration changes: starter (Table 5), grower (Table 26) and finisher (Table 27). 

AD researchers do not follow the same procedures; it has been necessary to make some 
arbitrary decisions as to which experiments to include in each summary. Table 5 includes 
those experiments in which pigs weighed less than 35 pounds initially and were continued 
on the diets to a maximum weight of 75 to 80 pounds. The summary for the grower 
phase (Table 26) includes those experiments in which pigs weighed more than 35 pounds 
and were continued on experiment until they weighed 125 to 150 pounds. The growing- 
finishing summary includes data to market weight (Table 27). 

As is commonly observed, the responses are much greater during the starter phase and 
decline as the pig matures. This is particularly noticeable if the differences are expressed 
as a percentage of the controls. For example, the differences between controls and pigs 
supplemented with antibiotics in mean daily gain for all experiments is 0.14 pounds per 
day for both the starter and the grower phase (Table 5 and 25). However, when expressed 
as a percentage of the mean daily gain by control pigs, the 0.14 represents 16.09% improve- 
ment during starter phase and 10.69% improvement during the grower phase. 

It is obvious from the results presented in the tables that all antibiotics are not equally 
effective for swine. Even though a drug may be approved by the Food and Drug Adminis- 
tration as an additive to improve rate and efficiency of gain, there is no required assurance 
that it be equally effective or superior to the previously approved antibacterials. Similar 
differences in responses were reported in 1953 by Braude et al. (Table 28) and in 1954 by 
Lasley et al. (Tables 29 and 30). 



34 



TABLE 28 

GROWTH AND FEED EFFICIENCY IN DIETS OF GROWING-FINISHING PIGS 
FED DIETS FORTIFIED WITH VARIOUS ANTIBIOTICS ^ 



Antibiotic 

Chlortetracycline 

Oxytetracycline 

Penicillin 

Streptomycin 

Bacitracin 

Chlormycetin 

Neomycin 



^Adapted from Braude et al, 67. 

TABLE 29 
RESPONSE BY WEANLING PIGS FED ANTIBIOTICS IN DRY LOT^' ^ 



No. Comparisons 


Improvement in 
Performance, % 


ADG 


F/G 


ADG 


F/G 


187 


146 


36 


9.8 


23 


17 


24 


6.1 


53 


44 


11 


5.7 


50 


41 


15 


5.6 


12 . 


10 


9 


-7.0 


6 


3 


6 


1.7 


4 


4 


-7 


12.4 



Number of 




Improvement in 


Perfo 


rmance, % 


Experiments 


Antibiotic 


ADG 




F/G 


24 


Chlortetracycline 


18 




3.5 


8 


Oxytetracycline 


17 




2.5 


5 


Penicillin 


18 




5.3 


9 


Streptomycin 


17 




5.5 


2 


Bacitracin 


2 




2.6 


48 


Average 


17 




3.9 



^Includes experiments in which pigs were fed to near 200 pounds body weight. 
^Adapted from Lasley et al. (289). 



35 



TABLE 30 

EFFECTS OF ANTIBIOTICS ON PERFORMANCE AND SURVIVAL 
OF GROWING-FINISHING PIGS^ 





Antibiotic 


Pigs 
Started " 




Controls 


+ Antibiotic 


Weiglu, lb. 
Initial Final 


No. 
Pigs 


ADG F/G 


No. 

Pigs ADG F/G 



43 
68 
64 

52 
35 
35 
44 
60 
43 
44 
50 



171 
208 
193 
155 
174 
176 
180 
192 
175 
182 
187 



Penicillin 

Streptomycin 

Chlormycetin 

Chlortetracycline 

Penicillin 

Chlortetracycline 

Penicillin 

Penicillin 

Chlortetracycline 

Chlortetracycline 

Chlortetracycline 



20 
40 
30 
16 
14 
14 
20 
50 
20 
20 
30 



20 
38 
27 
13 
13 
13 
20 
47 
20 
20 
29 



1.38 
1.68 
1.45 
.98 
1. 10 
1.10 
1.48 
1.49 
1.37 
1.47 
1.40 



3.95 
3.92 
3.81 
5.34 
3.98 
3.98 
3.95 
3.80 
3.95 
3.95 
3.76 



19 
40 
30 
15 
14 
13 
20 
49 
20 
20 
29 



1.38 
1.77 
1.55 
1.21 
1.32 
1.30 
1.46 
1.64 
1.45 
1.52 
1.78 



3.70 
3.64 
3.67 
4.34 
3.58 
3.63 
3.63 
3.67 
3.61 
3.70 
3.41 



Total Pigs 

% Survival 

Avg. daily gain & avg. feed/gain 

% Improvement 



274 



260 
94.9 



1.35 4.03 



269 
98.2 

1.49 
3.5 10.4 



3.69 

8.4 



^Adapted from Lasley et al. (289). 
Per treatment. 



It is obvious from these summaries that antibacterial agents are not equally effective in 
improving growth rate and feed efficiency. In general, those of a broader antibacterial 
spectrum (singly or in combinations) are more effective. 

Copper sulfate is used extensively in Great Britain as a feed additive and has been tested 
thoroughly in this country. When copper sulfate is added at a dietary level of 250 pprn of 
elemental copper, an additive effect of antibiotics is usually not observed, indicating a 
similar mode of action for the copper and antibiotics. Petitions to our regulatory agencies 
for similar use in this country have not been approved, with certain concerns being 
expressed about increased copper levels in tissues and adding excess copper to the environ- 
ment. These are complicated and debatable issues and beyond the scope of this paper. The 
experimental work on effects of copper on growth rate and feed conversion has been 
thoroughly reviewed by Braude (63) and is summarized in Tables 31 and 32. As with anti- 
biotics, there are variations among reports on the actual magnitude of rate of gain and 
feed/gain responses. In Braude's review, the average improvement in rate of gain was 8.7% 
and for feed conversion, 6.6% when copper (250 ppm) was added to the diet. Lower 
levels of copper resulted in responses of a lower magnitude (Table 31). 



36 



TABLE 31 
RESPONSE OF PIGS TO VARYING LEVELS (PPM) OF DIETARY COPPER^ 

Improvement in Performance, % 



Level of 


Number of 


Cu, ppm 


Experiments 


125 


38 


150-180 


10 


200 


7 


250 


202 



Average Daily Gain 



Feed/Gain 



4.4 
3.6 

4.4 

8.7 



3.4 
3.1 
3.9 
6.6 



^Adapted from Braude (63). 

The average responses for 1955-1965 and 1965-1975 were quite similar (Table 32). 

TABLE 32 
EFFECTS OF COPPER (250 PPM) ON PERFORMANCE OF PIGS^ 





No. 
Experiments 


Total Pigs 
Per Treatment 


Improvement in 
Performance, % 


Time Period 


Average Daily 
Gain 


Feed/Gain 


1955-65 
1965-75 


83 
119 


1215 
2630 


8.1 
9.1 


5.4 

7.4 



^Adapted from Braude (63). 



It is obvious that some of the gains in production efficiency attributed to antibiotics 
could be achieved by the use of other antimicrobial agents such as copper compounds, 
arsenicais, nitrofurans and carbadox; however, the trade-offs in absolute efficacy or safety 
have not been thoroughly researched or discussed. Restricting the use of one or a few 
agents will naturally result in greater use of those not similarly restricted. The use of 
other agents, which have not been thoroughly evaluated over an extended period, may be 
more detrimental than the concerns presently being expressed about tetracyclines and 
penicillin. 



37 



There is ample evidence that species, age of animal or stage of production, adequacy of 
diet and environmental conditions are all important factors affecting the response to anti- 
biotics. Each of these factors must be considered when selecting an antibiotic to use, level 
to feed and duration of feeding. The examples in the sections on "Mode of Action" and 
"Continued Effectiveness" will serve to illustrate effective application in feeding programs. 
Only a few additional comments and illustrations of particular benefits regarding swine 
will be presented. 

The use of a high level of antibiotics in the diet of sows at breeding time increases concep- 
tion rate and litter size. Table 33 summarizes a number of studies that involved more than 
1300 sows and show an average 7% improvement in conception rate at tust estrus and 0.4 
more live pigs farrowed per litter. 



TABLE 33 

THE EFFECT OF ANTIBIOTICS AT BREEDING TIME 
ON FARROWING RATE AND LITTER SIZE 



No. 


Farrowin; 


g Rate, % 


Live Pig 


,s/Litter 




Sows 


Control 


Treated 


Control 


Treated 


Reference 


377 


68.5 


82.9^ 


9.8 


10.1^ 


Messersmith et al., 342 


59 


- 


- 


7.1 


9.7b 


Dean and Tribble, 144 


96 


87.5 


95.8^ 


9.0 


10.3^= 


Ruiz etal., 433a 


182 


60.9 


70.0^^ 


9.8 


lO.O'^ 


Krug, 287 


249 


66.9 


75.4^ 


9.9 


10.2^ 


Myers and Speer, 372 


192 


93.8 


91.6^ 


10.9 


11.3d 


Mayrose et al., 323 


239 


70.8 


72.3 


10.2 


10.4 


Soma & Speer, 49 1,490 


Weighted 

Avg. 


72.6 


80.0 


9.9 


10.3 





^Chlortetracycline, 0.5 to 1.0 g/sow/day. 

^Chlortetracycline, 0.5 to 1.0 g/sow/day, 0.54 g/sow/day. 

'^Chlortetracycline, sulfamethazine and penicillin at 0.5, 0.5 and 0.25 g/sow/day, 
respectively. 

Tylosin phosphate, 0.6 g/sow/day. 



38 



Speer (493) summarizes additional unpublished data on both tetracycline and tylosin 
which in some cases show an even larger difference in conception rate than shown in Table 
33. A high level of an absorbable antibiotic seems necessary to elicit this response. This 
is reasonable since conception rate or litter size problems are likely associated with sys- 
temic rather than gastrointestinal problems. Using embryo survival to 28 days as an indi- 
cator of reproductive performance, Sosa et^al. (492) reported that tylosin improved the 
number of live embryos but that bacitracin did not. Neither of these antibiotics are 
particularly well absorbed, but tylosin appears to be more effective against systemic 
infections. 

Young growing pigs show a markedly greater and more consistent response to antibiotics 
than do more mature animals. Table 34 provides a typical illustration of the greater 
response of very young pigs as compared with that of older pigs. 



TABLE 34 

EFFECT OF FEEDING OLEANDOMYCIN AT DIFFERENT LEVELS 
ON PERFORMANCE OF PIGS^ 



Pigs Tested and 
Level of Olean- 
domycin Fed 


Average 
Initial 


Wt. (kg) 
Final 


Daily Gain 


Feed Efficiency 


Average 

(%) 


Improve- 
ment (%) 


Average 


Improve- 
ment (%) 


Baby pigs'^ 














No oleandomycin 


4.29 


8.91 


163 




2.02 




2.5 g/ton 


4.18 


10.13 


213 


30.7 


1.73 


14.4 


5 g/ton 


4.10 


10.07 


213 


30.7 


1.62 


19.8 


10 g/ton 


4.34 


10.70 


227 


39.3 


1.69 


16.3 


20 g/ton 


4.35 


10.98 


236 


44.8 


1.62 


19.8 


Growing pigs 














No oleandomycin 


13.26 


34.41 


527 




2.82 




5 g/ton 


13.35 


36.18 


572 


8.5 


2.60 


7.8 


10 g/ton 


13.21 


35.96 


563 


6.8 


2.52 


10.6 


20 g/ton 


13.44 


35.87 


563 


6.8 


2.63 


6.7 



^Hawbakere^al.. (209). 

Units of feed per unit of gain. 
''Initial age 13 days. 

Initial age 5 1 days. 



39 



Oleandomycin was fed to the two groups of pigs. In baby pigs, the antibiotic resulted in 
an increase in growth rate of 30%- to 44% and an improvement in feed efficiency of 14% 
to 20%. In the older pigs, the antibiotic resulted in an improvement of 7% to 10% in 
growth rate and efficiency. This age effect is further illustrated by the data in Tables 
5, 26 and 27. 

The diets used today to evaluate the effectiveness of antibiotics are, in general, more 
adequately balanced to meet the animals' needs than were the diets used in the early 
1950's. There are two main reasons for this: more information is available regarding the 
nutrient needs; some nutrients, particularly the vitamins, are less expensive today. The 
feeding of nutritionally balanced diets reduces but does not eliminate the response to anti- 
biotics. Certain developments may have offset some of the gains made possible by greater 
knowledge about nutrient requirements. For example, the performance of pigs during the 
starter phase in 1957 to 1966 is not as good as in 1950-1956 (see bottom of Table 5). 
During the early 1950's most early weaned pigs were started on diets high in milk 
products. The cost of milk products has resulted in a reduction in the use of this higlily 
digestible source of protein and carbohydrate. The diet changes probably explain the 
greater response in antibiotics in 1957-1966 as compared with 1950-1956. Another 
illustration in the tables which should be noted is the improvement in feed/gain ratios 
with time for the growing-finishing pigs. If the data is averaged for penicillin-streptomycin, 
tetracyclines and bacitracin, there has been a 9.6% change in feed conversion of control 
animals as compared with a 6.0% for the antibiotic treated animals. Assuming that 
the genetic potential is the same for the antibiotic treated and control groups, the data 
support the earlier cited observations of Waibel et d. (556) and Libby and Schaible (296) 
that a portion of the reduction in percentage responses is a result of improvement of the 
controls rather than a decline in the effectiveness of the antibiotic. 

A statistical evaluation of the tetracychne data (120 experiments) in Table 26 revealed no 
significant year by treatment interaction for feed/gain ratios. There was a significant linear 
improvement in feed conversion with time (0.01 1 Ib/yr) with a constant predicted improve- 
ment (P<01) of 0.10 lb. of feed per pound of gain for the treated group as compared with 
controls. There was evidence of a treatment by year interaction for rate of gain. Regres- 
sion analysis showed no significant change with time for the treated group, but a signifi- 
cant increase in growth rate of controls to 1962 and a constant rate thereafter. The initial 
difference in 1950 was about 0.2 lb. per day; this difference declined to approximately 
0.08 lb/day by 1962 and remained constant thereafter. This improvement in performance 
of controls relative to no change in performance of treated animals is consistent with the 
previously cited observations of Waibel et _al_. (556) and Libby and Schaible (296) for 
poultry. The observation was probably first expressed, but not published to my knowledge, 
by the late Damon V. Catron. 

The improvement in feed/gain ratios accompanied by little, if any, change in rate of gain 
with time reflects the selection emphasis in the swine industry. More selection pressure 
has been put on reducing fatness in pigs. This leads indirectly to a reduction in total feed 
required per unit of live weight gain. This has probably had an even greater impact on 
reducing feed required per unit of gain than any direct efforts to select for improved 
efficiency. 



40 



Hygienic conditions in swine production have not greatly improved in recent years. Though 
greater knowledge about the role of hygiene in animal performance has been gained and 
producers are expending greater effort in this regard, other changes in systems of produc- 
tion have occurred that partially offset the advances made in sanitation practices. These 
changes have been necessitated by the increased value of land and a marked reduction in 
available labor. Producers are finding it necessary to specialize in fewer livestock enter- 
prises and to confine their animals to smaller spaces in order to release land for alternative 
uses and to facilitate the mechanization of feeding and disposing of wastes. 

Such intensification of production accentuates some of the environmental factors affect- 
ing responses to antibiotics. The increased concentration of animals in limited space can 
lead to a higher incidence of clinical and subchnical disease because of the greater ease of 
transmittal. Fortunately, the use of antibiotics has contributed to the success of many of 
these intensive units. Feed additive usage results in the greatest responses during periods 
of natural or imposed stresses. In pigs the greatest responses are observed at breeding or 
farrowing in sows, at weaning in young pigs and during the stresses associated with reloca- 
tion, such as movement of feeder pigs. Similar situations apply to other species. 

V. Effectiveness of Antibacterial Agents in Feeding Programs for Growing Chicks and 
Layer Hens 

The factors affecting the response of chickens to antibiotics are similar to those affecting 
the responses by pigs. The management programs are, however, very different. Because of 
the ability to provide nearly unlimited day -old chicks at a given time, much more rigorous 
control over the genetic background of the chicks, the management procedure of all-in, 
all-out systems of productions, different disease and parasite problems, and the many 
other differences in production procedures and problems, it is obvious that the need for 
and conditions for use differ markedly between poultry and swine. 

The antibacterial agents which are useful for the two species are generally the same. It 
does appear that certain drugs, for example bacitracin and penicillin alone, are more effec- 
tive in poultry than in swine. In swine feeding programs the application of bacitracin has 
been limited primarily to the growing-finishing stage, whereas in chicks it has been used 
extensively in the starter stage. Penicillin has been used very extensively in poultry feed- 
ing programs; it has usually been used in combination with other drugs (streptomycin, 
bacitracin, chlortetracycline, etc.) in swine feeding programs. 

The examples cited illustrate the responses of growing chicks to antibacterial agents. These 
responses are summarized in more detail in Table 35 for chicks to about four weeks of 
age and in Table 36 for chicks to approximately eight weeks of age. 



41 









TABLE 


35 








SUMMARY OF CHICK PERFORMANCE TO ABOUT 4 WEEKS 








CI 


liick Wt. 




Feed/Gain 




Antibiotic 


n^ 


- 


+ 


% Imp.^' n^ 


- 


+ 


'^ imp.*^ 


Tetracycline 


174 


397.2'^ 


426.3*^ 


7.33 106 


2.16'^ 


2.05^^ 


5.09 


Penicillin^ 


155 


334.1 


361.2 


8.11 77 


2.02 


1.93 


4.46 


Bacitracin 


73 


418.6 


445.0 


6.30 34 


1.85 


1.79 


3.24 


Arsenicals^ 


61 


354.6 


372.1 


4.94 16 


2.14 


1.99 


7.01 


Streptomycin'"' 


17 


472.5 


506.8 


7.26 11 


2.64 


2.59 


1.89 


Virginiamycin' 


10 


233.4 


270.7 


15.98 4 


2.54 


2.31 


9.06 


Nitrofurans) 


8 


408.5 


395.1 


-3.28 1 


1.53 


1.57 


-2.61 


Oleajidoniycin 


26 


459.4 


482.4 


5.01 23 


1.78 


1.74 


2.25 


Lincomycin 


6 


344.8 


376.7 


9.25 6 


1.57 


1.44 


8.28 


Bambermycins'^ 


24 


485.5 


503.8 


3.77 24 


1.67 


1.64 


1.80 


Erythromycin" 


7 


334.6 


358.7 


7.20 7 


1.98 


1.88 


5.05 


Tylosin^ 


4 


277.0 


284.8 


2.82 4 


2.00 


1.98 


1.00 


Weighted avg. 


565 


382.0 


407.7 


6.72 313 


2.03 


1.94 


4.43 



^ n = number of comparisons (experiments). 

Percentage improvement in performance due to antibiotics. 

''Average weight (g) per bird and feed/gain for birds fed diets without (-) or with (+) 
antibiotics. 

'^ChJortetracycline and oxytetracycline. References: 40, 44, 48, 106, 132, 133, 140, 
153a, 164, 178, 188, 192,225,227,230,282,303,307,311,314,321,361,373,393, 
401, 432, 442, 450, 451, 452, 469, 489, 506, 507, 527, 539, 567, 569, 592, 593, 596. 

^References: 1, 41, 60, 1 12, 132, 140, 164, 168, 170, 172, 188, 225, 227, 230, 233, 235, 
261, 269, 295, 307, 314, 318, 319, 321, 352, 361,367,379,414,442,462,484,506, 
526,527,539,567,576,596. 

^References: 41, 106, 140, 168, 169, 171, 178, 188, 225, 307, 321, 318, 319. 320, 352, 
361 , 379, 392, 414, 527, 539, 567, 569, 596. 

^References: 1,87, 168, 169, 171,295,320,367,400,450,461,556,591. 

'^References: 140, 192, 225, 227, 261, 361. 

'References: 163, 164,379. 

J References: 177,368. 

•^References: 314,361,462,586. 



42 



' References: 319, 320. 321. 352. 
'"References: 133. 310. 321. 352. 561. 
"References: 361. 379. 527. 596. 
'-^References: 361.379.527. 



TABLE 36 
SUMMARY OF CHICK PERFORMANCE TO ABOUT 8 WEEKS 







Ch 


lickWt. 






Feed/Gain 




Antibiotic 


n^ 


- 


+ 


-? Imp.^^ 


n^ 


- 


+ 


'T Imp.'^' 


Tetracvcline*" 


88 


1192.1^' 


1236.1^' 


3.69 


53 


2.60^^ 


2.54^^ 


2.31 


Penicillin^ 


54 


1299.2 


1337.3 


2.93 


38 


2.54 


2.47 


2.76 


f 
Bacitracin 


39 


1425.2 


1438.7 


0.95 


33 


2.27 


T T) 


2.20 


Arsenicals^ 


59 


1285.5 


1329.7 


3.44 


50 


2.54 


2.46 


3.15 


Bambemiycins'^ 


32 


1483.3 


1517.9 


2.35 


32 


2.06 


2.02 


1.94 


Lincomvcin' 


4 


1734.5 


1812.2 


4.48 


4 


2.12 


2.05 


3.30 


NitrofuransJ 


3 


1414.3 


1442.3 


1.98 


-) 


2.05 


2.02 


1.47 


Oleandomycin 


7 


1483.0 


1549.4 


4.48 


7 


2.25 


2:21 


1.78 


Total Number 


286 








219 








Weighted Avg. 




1313.0 


1351.6 


2.94 




2.42 


2.36 


2.48 



Number of comparisons (experiments). 

Percentage improvement in performance due to antibiotic. 

^Average weight (g) per bird and feed/gain for birds fed diets without (-) or with ( + ) antibiotics. 

^Ciilortetracvcline and oxvtetracvcline. References: 106. 133. 141. 178. 339. 442. 450. 472. 
489. 572. 573. 574. 583, 592, 5%. 

^References: 261,295,319,339,321,414.442,462,472,572,573,574. 

'References: 42. 106. 135. 141, 178,251,319,320,321.339.414.572,574.585. 

^References: 135. 141. 171. 274, 275, 295, 318, 320, 351, 354. 400,421,450, 572. 

'^References: 133, 274. 275. 319, 321, 561. 

'References: 319,320,321. 

J References: 368. 



References: 462. 



43 



.•\s was the case for the comprehensive summaries of swine data, researchers do nt)t use 
the same length of trials, same diets, etc. Those e.xperimeiits involving diets which greatly 
exaggerate the responses were e.xcluded from these sununaries. Certain dietary ingredients 
such as rye, improperly toasted soybean meal. etc.. greatly exaggerate responses to anti- 
biotics. These diets may be particularly helpful in screening antibacterial agents for effec- 
tiveness or the antibacterial agents may be beneficial in using such ingredients. The inclu- 
sion of these experiments in the summary ct)uld give a somewhat distorted evaluation of 
the overall effectiveness. 

in Table 35 the weighted average of 5(i5 experiments, which involved thousands of chicks, 
shows an average of 6.72 percent improvement in weights. In 31 3 of those experiments, 
data were also presented for feed required per unit of gain; the average response was 
4.43'/. Similar summaries to approximately iS weeks of age were 2.94''f improvement in 
chick weights and 2.48'^ improvement in feed conversion (Table 36). 

There are differences in final average weights for the control birds for the different anti- 
biotics presented in the summary. A part of these differences in weights can be related to 
the time span over which the antibiotics were tested and a part can be attributed ti) the 
fact that the summaries involved both layer breeds and broiler breed chicks and for some 
antibiotics a higher proportion of the experiments in the summary involved broiler breeds. 
For example, the experiments with lincomycin are limited to 1974-1977, whereas the tests 
with tetracyclines and penicillin cover the entire period of usage, 1950 to 1977. During the 
past 27 years tremendous genetic improvements in rate of weight gain and efficiency 
of feed conversion have been made, in the early 1950"s it took more than 10 weeks to 
produce a 3.5 pound broiler and required 3.0 pounds of feed or more per pound of gain. 
Now. it takes less than 8 weeks time and the feed conversii)n may be 2 pounds of feed 
per pound of gain or less. 

The mean responses presented in Tables 35 and 36 illustrate the effectiveness of the drugs 
in improving bird weiglits and feed conversion. 

Summaries of the percentage responses to antibiotics since 1970 in comparison with all 
years are presented in Tables 37 and 38. 

TABLE 37 

IMPROVliMHNT IN (HICK PERFORMANCE - ALL YEARS VS. SINCE 1970 
(TO APPROXIMATELY 4 WEEKS OF AGE)^ 





Wei gilt. 


, g 






Fee 


■d/G; 


ain 




All \'ears 


Since 
No. 


19 70 
''■ Imp. 


All ^' 


ears 




Since 1970 


Antibiotic 


No. '' imp. 


No. ' 


' Imp. 


No. ''< Imp. 


Tetracycline 


174 7.33 


24 


6.79 


106 


5.09 




19 5.38 


Penicillin 


155 8.11 


45 


12.20 


77 


4.46 




28 7.14 


Bacitracin 


73 6.31 


40 


7.34 


34 


3.24 




17 2.75 


Arsenicals 


61 4.94 


25 


4.71 


16 


^.01 




S 4.81 



^Data from Table 35. 



44 



TABLE 38 

IMPROVEMENT IN CHICK PERFORMANCE - ALL YEARS VS. SINCE 1970 
(TO APPRO.XIMATELY 8 WEEKS OF AGE)^ 







Weight 


2 






Feed/G 


lain 




All Years 


Since 


1970 


All Ye 


ars 


Since 1970 


Antibiotic 


No. 


% Imp. 


No. ^ 


r Imp. 


No. ^r 


Imp. 


No. % Imp. 


Tetracycline 


88 


3.69 


17 


1.65 


53 


2.31 


14 2.04 


Penicillin 


54 


2.93 


11 


1.99 


38 


2.76 


1 1 2.93 


Bacitracin 


39 


0.95 




2.72 


33 


2.20 


22 2.42 


Arsenicals 


59 


3.44 


18 


1.54 


50 


3.15 


18 1.41 



^Data from Table 36. 



There is some variation but. in general, these summaries illustrate continued etTectiveness. 
There have been many changes, as discussed previously, in the industry during that time 
span, and these changes can affect the magnitude of the response. To approximately 4 weeks 
of age. the average response to penicillin ( 12.20 vs. 8.1 \'r) and bacitracin (7.34 vs. 6.3r7) 
is higher for the time period since 1970 than for the overall period. For tetracyclines 
(6.79 vs. Ijy.'t) and arsenicals (4.71 vs. 4.94^7) the trend is in the opposite direction. 
For feed conversion, the average response to tetracycline (7.14 vs. 4.46%) is greater since 
1970 than for the entire time span. The average feed/gain response to bacitracin (2.75 vs. 
3.24%) and to arsenicals (4.81 vs. 7.01 y) is in the opposite direction. If all the environ- 
mental and genetic variations that existed in these indirect time comparisons were subject 
to critical evaluation, the real change in magnitude of response could possibly be deter- 
mined. These data illustrate, however, the continued effectiveness of all four antibacterial 
agents. Table 38 presents a similar summary for chicks to 8 weeks of age. These data are 
possibly more consistent with the e.xpected change in response to antibacterial agents 
over time with chicks. The progress accomplished in controlling some of the major poultry 
diseases including coccidiosis. the improvements in diet formulations and the improve- 
ments made in housing and ventilation should all contribute to a lower response to the 
antibacterial agents; however, there is evidence of continued effectiveness. These sum- 
maries are generally consistent with the conclusions of Bird (46). He limited his summary 
to broiler breed chicks and to experiments which continued to market weight and con- 
cluded that data t>om 1951 to 1968 did not show any trend toward decreased effective- 
ness of the four antibiotics (chlortetracycline, ox\'tetracycline, penicillin and bacitracin) 
having the longest history of use. 

There is less data available for layer and breeder hens. Table 39 presents a summary of 
these data. 



45 



TABLi; 39 

SUMMARY OF ICiCi PRODUCTION. 
Plil-D PI:R DOZliN LCiGS AND HATCIIABILITY 





Lgg I'ro 


Juction. '"( 
+ '/< Imp. 


{■Ci 


'd/do/. r.ggs 


.lb. 


1 


latch 


ibilit\ 


'■; 


Antibiotic 


11 




+ ' 


Imp. 


n 




+ ' 


'< Imp. 


Tetracycline ^ 


^^ 


52.9 


59.2 


1 1 .9 1 


1 -1 


5.50 


5.01 


8.91 


16 


74.9 


76.0 


1.47 


Arsenicals*" 


33 


59.8 


61.2 


2.34 


30 


5.43 


5.36 


1.29 


17 


72.3 


76.5 


5.81 


Penicillin^ 


27 


54.3 


57.3 


5.52 


19 


5.75 


5.46 


5.04 


13 


75.6 


78.6 


3.97 


Bacitracin'' 


12 


63.2 


63.8 


0.95 


5 


4.38 


4.28 


2.28 


-) 


74.6 


79.8 


6.97 


Fiainberinycins' 


5 


47.8 


52.0 


8.79 


5 


7.50 


6.62 


11.73 


1 


84.2 


86.3 


2.49 


lirythroinycin^^ 


37 


66.4 


67.3 


1.36 


13 


4.42 


4.36 


1 .36 


7 


84.6 


84.9 


0.35 


Others and 


























Combinations ^ 


01 


62.1 


63.9 


2.90 


28 


4.89 


4.64 


5.1 1 


13 


78.6 


81.7 




Weighted avg. 


244 


59.9 


62.3 




122 


5.30 


5.05 




69 


76.2 


78.8 




Avg. Improvement 


fV 






4.01 








4.72 








3.41 



''Number of comparisons of hens fed diets without (-) or with ( + ) antibiotics. 
'^Chlortetracyciine and o.xytetracycline. Referencs: 10. 41. 52. 62. 90, 133. 136. 162. 

226, 228. 229. 231. 404. 438. 463. 471. 528. 
'^References: 10. 11. 18, 85. 136, 143, 226, 228. 295, 301, 410, 529a, 575. 
^References: 41. 52. 76. 85. 91. 125a, 133, 143. 155. 156. 228. 301, 370. 404. 405, 

463, 529a. 

^References: 41.86, 156, 226, 252. 
f 
Reference: 1 2>}). 

^References: 136, 193. 194, 226, 382, 383, 415. 

'^Ret^erences: 10, 1 1, 85. 91. 125a, 136, 143, 193, 194, 226, 228. 243. 286. 336. 387, 

389,404,441,463. 529a. 



No attempt was made to separate time comparisons, as the available data is for the most 
part limited to the early years of the introduction of antibacterial agents into the feeding 
program. Most of the data on tetracvclinc and penicillin is from the 19S()'s; lor erythriv 
mycin. frt)m the 19(-)0"s; and tor bambermvcin, from the l'-'70"s. In this table. 9| expeii- 
ments were included in a grouping ot others plus combinations. This grouping included 
drugs or combinations that were never approved plus those lor which there ma\ have 
been niininnim data, and is only included to add credence to ihe othei observations that 
antibacterial agents are beneficial. 



46 



The weiglited average responses to the antibacterials hsted were 4.01 , 4.72 and 3.41% for 
egg production, feed required per dozen eggs and percent hatchability, respectively. Many 
of the experiments were based on a full laying-year period for the egg production and 
feed conversion. For hatchability, the data were frequently limited to much shorter 
periods. These overall average responses included only those experiments (as was the case 
for the growing data) for which the diets were formulated to be nutritionally adequate 
and did not include dietary ingredients that would exaggerate the response. There is the 
consistent opinion among researchers, as expressed in the literature, that the magnitude 
of the response is markedly influenced by temperature, humidity and other environmental 
stresses. Extreme cold weather(Ryan et a]., 438; Nivas et al., 382) or extreme hot weather 
(Heywang, 228, 229, 231), which cannot be completely avoided due to year-around 
production in all areas of the country, increases the response to antibiotics. 

A summary of field experiments by Melliere (336) is presented in Table 40. 



TABLE 40 
EFFECT OF TYLOSIN ON EGG PRODUCTION^ 







Treatment 




Imp 


rovement 


Item 


Controls 




Tylosin 


c 


No. trials 


14 




14 






Hens per treatment 


96,618 




101,374 






Eggs/hen 


172.1 




175.6 




2.0 


Feed/doz. eggs, kg. 


2.89 




2.79 




3.5 



Summary of 14 field trials, Melliere (336). 



The averages of 2.0% improvement in egg production and 3.5% improvement in efficiency 
of feed conversion are similar in magnitude to that of the later stages of broiler production. 

VI. Effectiveness of Antibacterial Agents in Feeding Programs for Turkeys 

Potter (412) summarized the response of turkeys to antibiotics to the year 1971. For the 
starter period (0 to 4 weeks of age) he reported an average of 19.3 and 18.2% improve- 
ment in gains and 7.3 and 7.6% improvement in feed conversions for penicillin and tetra- 
cycline, respectively. To 8 weeks of age the responses were 18.1 and 16.8% improvement 
in gains and 1 0.0 and 10.1% improvement in feed/gain for penicillin and tetracycline, 
respectively. Potter reported on a few experiments in which the turkeys were taken to 
market weight. For penicillin the average response was 5.2 and 8.6% for gain and feed/ 
gain response, respectively. Comparable data for tetracycline were 3.2 and -1.2%. 



47 



SuiiiiiKiry Tables 41 . 42 and 43 piesciit average responses to several anlibiolics. 



TABLi; 41 



RispoNsi; or turkizys to antibiotics 

(TO APPROXIMATl-LY 4 WIIEKS 01 AGH) 





n' 


We 


igiit, g 
+ 


Imp. '' 




Feed/Gain 




Antibi(.)iic 


n3 




+ 


Imp. % 


Teiracwiine 


64 


470 


540 


14.89 


28 


2.03 


1.86 


8.37 


Penicillin"' 


53 


503 


580 


15.31 


18 


1.78 


1.64 


7.87 


Bacitracin 


32 


489 


537 


9.92 


23 


1.70 


1.62 


4.71 


Streptomycin'"' 


17 


516 


558 


8.14 


7 


1.92 


1.83 


4.69 


Number 


166 








76 








Weighted avg. 




4S9 


554 






1 .86 


1.73 




Improvement, ''i 








13.29 








6.98 



^Number of experiments in which turkeys were ted diets without (-) or with ( + ) 
antibiotics. 

''References: 5. 61.116. 140. .^>03. 328. 329. 330. 361. 394. 399. 442. 

""References: 61 . 116. 140. 283. 308. 328. 329. 330. 361 . 394. 442. 443. 454. 468. 476. 
477^ 479. 481. 500. 558. 570, 598. 

"^References: 105. 116. 206. 361, 363, 419, 442, 454, 516, 559. 568. 

"^References: 61. 140. 283, 328, 330, 361, 394, 559. 



48 



TABLE 42 

RESPONSE OF TURKEYS TO ANTIBIOTICS 
(TO APPROXIMATELY 8 WEEKS OF AGE) 









We 


ight. g 


Imp. 7c 


na 


Feed/Gain 

- + 




Antibiotic 


n^ 


- 


+ 


Imp. % 


Tetracvcline 




31 


1453 


1645 


13.21 


27 


2.38 


2.24 


5.88 


Penicillin'" 




24 


1270 


1400 


10.24 


12 


2.49 


2.35 


5.62 


Bacitracin 




55 


2031 


2132 


4.97 


45 


1.83 


1.78 


2.73 


Bambermycins^ 




16 


3755 


3931 


4.53 


16 


1.97 


1.92 


1.92 


Number 




126 








100 








Weighted avg. 






1963 


2101 






2.08 


2.00 




Improvement, 


% 








7.03 








3.85 



'^Number of experiments in which turkeys were fed without (-) or with ( + ) antibiotics. 

'^Chiortetracycline and oxytetracycline. References: 6, 12, 13, 61, 399, 453, 482, 483. 
515, 554, 588. 

^^References: 13,61. 266,309,442.444,473,482, 515,589. 

^References: 19,413,417.419,420, 515,516, 555,562,586. 

^16 weeks of age rather than 8. Reference: 355. 

TABLE 43 

RESPONSE OF TURKEYS TO ANTIBIOTICS 
(TO MARKET WEIGHT) 









Weight, lb. 


Imp. ^j 


n^ 


Feed/Gain 

— + 




Antibiotic 


n'^ 


- + 


Imp. 7c 


Penicillin^ 




5 


17.80 17.82 


5.73 


o 


4.54 


4.42 


2.64 


Bacitracin*" 




80 


19.93 21.37 


7.23 


75 


3.14 


3.09 


1.59 


Number 




85 






11 








Weighted 


avg. 




19.80 21.22 






3.18 


3.12 




Improvement, 7c 






7.17 








1.89 



^Number of experiments in which turkeys were fed diets without (-) or with ( + ) 
antibiotics. 

'^References: 309, 444, 473. 476. 481 . 

^'References: 19, 252,310,413.418,419. 513.555. 



49 



The average responses are similar to those reported by Potter. The average weight responses 
were 13.3. 7.0 and 1 .2f< I'or data to 4 weeks. 8 weeks and market weigiit (20 to 24 
weeks), respectively. Feed/gain icsponses were 7.0. 3.8 and 1 .9 for the same periods. 

Responses of egg production, feed/egg and hatchabilily are presented in Table 44. 

TABLE 44 

EFFECTS OF ANTIBIOTICS ON RATE AND EFFICIENCY OF 
EGG PRODUCTION AND HATCHABILITY IN TURKEYS'' 





Number 
E.xperiments 


Antibiot: 


ic-b 




item 




+ 


Improvement 


Egg production, 7c 


15 


44.2 


44.8 


1 .36 


Feed/egg, g 


9 


516 


483 


6.40 


Hatchabilily, % 


16 


70.0 


70.0 


- 



''References; 14, 16, 19, 88, 142. 474, 557. 
Turkey hens fed diets without (-) or with ( + ) antibiotics. 



Egg production was improved by 1.36% and feed/egg improved by 6.407f. Data available 
from 16 experiments indicate that antibiotics have little or no effect on hatchabilily. This 
differs from the results with chickens in which hatchability was improved an average of 
3.4%. 

VII. Effects of Antibiotics On Mortality and Morbidity 

There is much less published data available on mortality and morbidity than for rate and 
efficiency o^ gain. Most of the swine reports do not include such data, probably because 
of the relatively small number of animals per experiment. Maddock (312) summarized a 
series of field experiments involving the antibacterial combination of chlorletracycline, 
sulfamethazine and penicillin and reported that 3.17% of the control pigs died as compared 
with 2.21% of the treated pigs. Those figures are based on 49 separate experiments involv- 
ing 2,204 pigs. Table 30 includes mortality data for several antibiotic comparisons. The 
average mortality for the control groups was 5.1% as compared with 1.8% for the anti- 
biotic treated group, based on 274 pigs per group. For the experiments presented in 
Table 10, the experimental records show mortality figures of 8.5% for the control groups 
and 3.8% for the treated groups. These experiments involved a total t)f 616 pigs. 

White-Stevens and Zeibel (583) reported the mortality and condemnation rates for a 
large group of broilers (5,000 per treatment) on a farm where chronic respiratory disease 
was a recognized problem. Including chlortetracycline (100 g/ton) in the diet reduced 
mortality (2.8 vs. 10.7%), reduced culling or condemnation (0.1 vs. 1.3%), increased 
weight of birds (3.08 vs. 2.87 lb.) and markedly increased the total marketed weiglUs 
(14,933 vs. 12,4001b.). 



50 



A number of papers (02, 297, 2b}. 318, 351 . 35^). 365, 387, 404, 405, 410, 415, 438, 
440, 4b3) include data on mortality: the general trend is toward a reduction in mortality 
from having antibiotic in the teed. In most experimental situations, mortality is relatively 
low and the researchers are usually nt)t in a position to attribute mortality or survival to 
a specific dietary treatment and do not anticipate that their experiments will be included 
in a large summary in an attempt to assess average mortality. 

VIII. Summary 

Antibiotic feed supplements have now been used routinely and successfully in livestock 
and poultry priiduction for more than 27 years. As the worldwide demand for animal 
protein increases, the use of antibacterial agents will bectime increasingly important for 
maintaining an efficient and competitive livestock industry. Tlicre can be no doubt that 
antibiotics continue to provide substantial economic benefits to both the producer and 
consumer of meat, milk and eggs. 

The number of alternative antibiotics which have been proven etTective in improving per- 
formance is relatively small. These antibiotics are those often found to be most effective 
in treatment o\' diseases. This observation is ct>nsistent with the evidence which supports 
the thesis that antibiotics result in improved performance through their control or preven- 
tion of specific or nimspecific diseases. These observations are significant since one is not 
likely to find antibiotics that are both particularly usefiil in improving performance oi" 
animals and that have no application in treatment of diseases. Additives other than anti- 
bacterial may result in improved rate and efficiency of gain. However, since their mode 
of action will likely be ditTerent, these additives will not replace or substitute tor anti- 
bacterial agents. 

The magnitude of the response to antibacterial agents varies with stage of life cycle, stage 
of production and the environmental conditions to which the animals are exposed. The 
response is greater in young animals than in more mature animals. The response is greater 
during critical stages of production such as weaning, breeding, farrowing, or immediately 
post hatching in chicks and turkeys. Environmental stresses such as inadequate nutrition, 
crowding, moving and mi.xing of animals, poor sanitation and high or low temperatures 
also contribute to increased responses. Such stresses are ordinary and to a large degree 
unavoidable. 

A critical review of the average responses to the various antibacterial agents clearly 
indicates that there are marked differences in the magnitude and consistency of responses. 
In general, those with a broader spectrum of antibacterial activity and those that are 
effective against gram-negative bacteria result in the greatest and most consistent responses. 

Comparisons of the responses to antibacterial agents in recent years with responses in 
the early penod of use demonstrate that those extensively used are still of benefit in 
improving growth rate and efficiency. There is some evidence that the magnitude of the 
response has declined for some uses. In view of the progress in nutrition, housing, manage- 
ment, sanitation and other factors that affect the response to antibiotics, it is surprising 
that the decline is not greater. There is also evidence that consistent use of antibiotics 
results in actual improvement in performance of the control animals rather than regres- 
sion of treated groups. 



51 



IX. Research Needs 

The development of antibiotic resistance with loss in efficacy and possible compromise 
of therapy in humans and animals has been a primary concern since the introduction of 
antibiotics, it has been proposed that meat, milk and eggs from animals fed antibiotics 
contribute to the transterable drug resistance in the consumer. This assumption could be 
tested with proper interspecies experimentation. Carel'ul epicleiiiiological studies are 
needed to determine the source of antibiotic resistance in humans and to what degree 
that resistance originates in animals and their flora. Interspecies studies excluding humans 
could provide more satisfactt)ry evidence than is available now. but animal-to-human and 
human-to-human transfer studies are needed. 

There is evidence that resistance development and resistance transfer may be reduced or 
prevented by concurrent use of other drugs. The safety and efficacy of these should be 
fully studied. Llse of such drugs could lead to continued application of present drugs and 
could also extend or increase their therapeutic efficacy. 

Further research is needed to determine if chronic oral exposme of humans to antibiotics 
and low-level, feed-additive usage in animals compromises therapy in humans or animals. 
Even after extensive use of the tetracyclines and penicillin, they continue to be the pri- 
mary drugs of choice for prophylactic and therapeutic use. A restriction in prophylactic 
or feed additive usage would likely increase therapeutic use, leading to total use at or 
above the present level. There is a need to determine whether therapeutic use or low level 
is the major contributor to resistance levels. 

The modes of action for antimicrobial agents are still an area of major disagreement, it is 
recognized that animals are exposed to a very complex and ever-changing microflora; thus 
the specific modes of action may be complex and ever-changing. Little research effort has 
been devoted to the determination of the modes of action. This research could lead to 
alternative drugs or methods. 

A thorough evaluation of the relative efficacy of currently available and new drugs is 
needed. Data on the older drugs permit indirect comparisons of the relative etTects on 
performance, mortality and morbidity; much less data are available for direct compari- 
sons. Greater emphasis on field evaluation of antibiotics is needed. Numerous environ- 
mental factors which affect the response to antibiotics cannot be adequately simulated in 
a laboratory situation. It is possible only through field evaluation to accurately assess the 
economic impact from use or restriction of use of antibiotics on animal production. 

Considerable research has been devoted to the possible detrimental effects of drug use in 
animals on human health. There has been, however, little attention to the possible bene- 
ficial effects of antibiotic usage in animals on human health. Reduction in infections, 
abscesses, etc., may be of benefit to man and should be investigated. 

Finally, research should be continued on metlu)ds of improving performance of animals 
without the use of drugs. Genetic resistance to disease, immunization to disease organisms 
and improved environment are all possible means of circumventing the need for anti- 
microbial drugs in animal production systems. 



5: 



1. Abbott, O.J.. H.R. Bird and W.W. Cravens. 1954. Effects of dietary arsanilic acid on 
chicks. Poultry Sci. 33:1245. 

2. Allee, G.L. and R.H. Hines. 1972. Supplemental copper for growing-finishing swine. Kan- 
sas Agric. Expt. Sta. Swine Industry Day Rept. p. 25. 

3. Allee, G.L., R.H. Mines and B.A. Koch. 1976. Evaluation of antibacterial preparations on 
growth rate and feed efficiency of young pigs. Kansas Agric. Expt. Sta. Swine Industry 
Day Progress Rept. 283. p. 31. 

4. Allee, G.L. and D.A. Schonewels. 1973. Influence of various antibacterial preparations on 
rate and efficiency of gain by young pigs. Kansas Agric. Expt. Sta. Swine Industry Day 
Progress Report 203. p. 3. 

5. Almquist, H.J. and J.B. Merritt. 1951. Effects of vitamin Bjt and crystalline aureomycin 
on growth of poults. Poultry Sci. 30:312. 

6. Almquist, H.J. and J.B. Merritt. 1953. The value of antibiotic supplements for growth and 
feed conversion in diets for growing turkeys. Poultry Sci. 32:878. 

7. Al-Timimi, A. A. and T.W. Sullivan. 1972. Safety and toxicity of dietary organic arsenicals 
relative to performance of young turkeys. 1. Arsanilic acid and sodium arsanilate. Poultry 
Sci. 51:111. 

8. Anderson, G.W., J.D. Cunningham and S.J. Slinger. 1952. Effect of protein level and pen- 
icillin on growth and intestinal flora of chickens. J. Nutr. 47: 1 75. 

9. Anderson, G.W., S.J. Slinger and W.F. Pepper. 1952. Effect of dietary microorganisms on 
the growth and cecal flora of chicks. Poultry Sci. 31 :905. 

10. Andrews. D.K., H.R. Bird and M.L. Sunde. 1966. The effects of arsanilic acid on laying 
hens at three dietary protein levels. Part 1. Egg production. Poultry Sci. 45:838. 

1 1. Andrews, D.K., H.R. Bird and M.L. Sunde. 1966. The effects of arsanilic acid on laying 
hens at three dietary protein levels. Part 2. Fertility, hatchability, chick growth and blood 
spot incidence. Poultry Sci. 45: 1305. 

12. Atkinson. J.C, R.V. Boucher and E.W. Callenbach. 1954. The intluence of terramycin 
and aureomycin on growth, variability and efficiency of feed utilization in White Holland 
turkeys. Poultry Sci. 33:332. 

13. Atkinson. R.L. and J.R. Couch. 1952. Crystalline antibiotics in the nutrition of poults 
kept on raised screen fliuHs. Poultry Sci. 31:115. 

53 



14. Atkinson, R.L. and J.R. Couch. 1951. The effect of vitamin B|2, APF concentrate, 
aureomycin, streptomycin, liver "L" and fish meal on egg production and hatchability of 
broadbreasted bronze turkeys. Poultry Sci. 30:905. 

15. Atkinson, R.L. and J.R. Couch. 1951. Vitamin Bp, and APF concentrate, aureomycin. 
streptomycin, liver "L" and fish meal solubles in the nutrition of the poult. J. Nutr.44:249. 

16. Atkinson, R.L.,C.F. Hall. J.W. Bradley. J.H. Quisenberry, D.T. Card and J.E. Wachstetter. 
1967. Effect of tylosin on the reproductive performance of turkeys and the growth rate 
of their offspring. Poultry Sci. 46:735. 

17. Baldwin. B.B., M.C. Bromel. D.W. Aird. R.L. Johnson and J.L. Sell. 1976. Effect of diet- 
ary o.xy tetracycline on microorganisms in turkey feces. Poultry Sci. 55:2147. 

18. Balloun, S.L. 1954. Effect of high level aureomycin feeding on rate of egg production. 
Poultry Sci. 33:867. 

19. Balloun. S.L., D.L. Miller, L.G. Arends and CM. Speers. 1969. Effects of Dimetridazole 
and antibiotics on growth and reproduction in turkeys. Poultry Sci. 48": 171. 

20. Barnhart, C.E., R. Ayer and C.H. Nichols. 1960. Effects of feeding furazolidone to brood 
sows during gestation and lactation and subsequent performance of their pigs. Univ. of 
Ky. Animal Sci. Research Report, p. 89. 

21. Barnhart, C.E., H. Brown and T.VV. Cathey. 1956. High levels of antibiotics for pigs in dry 
lot. Univ. of Ky. Animal Sci. Research Report, p. 37. 

22. Barnhart, C.E. and T.W. Cathey. 1957. High levels of chlortetracycline for early weaned 
pigs. Univ. of Ky. Animal Sci. Research Report, p. 58. 

23. Barnhart, C.E., T.W. Cathey and M.D. Whiteker. 1958. Effects of furazolidone on the 
control of scours and on the growth of young pigs. Univ. of Ky. Animal Sci. Research 
Report, p. 7. 

24. Barnhart. C.E.,C.H. Chaney and J.R. Bingham. 1959. Feed additives for growing-finishing 
pigs. Univ. of Ky. Animal Sci. Research Report, p. 56. 

25. Barnhart, C.E., J.R. Overfield and S.J. Lowry. 1960. Feed additives for growing-finishing 
pigs fed on concrete and pasture. Univ. of Ky. Animal Sci. Research Report, p. 94. 

26. Barnhart, C.E., J.R. Overfield and S.J. Lowry. 1961. Virginiamycin fed to growing- 
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169. Fernandez, R., E. Lucas and J. McGinnis. 1973. Effect of diet on growth and feed 
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170. Fernandez, R., E. Lucas and J. McGinnis. 1973. Fractionation of a cliick growth 
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171. Fernandez, R., E. Lucas and J. McGinnis. 1973. Influence of diet composition on chick 
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172. Fernandez, R. and J. McGinnis. 1974. Nutritive value of Triticale for young chicks and 
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173. Fletcher, J.L. and B.F. Barrentine. 1954. Antibiotic supplementation of corn-cottonseed 
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174. Forbes, M.. W.C. Supplee and G.G. Combs. 1958. Response of germ-free and convention- 
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175. Foster, J.R.. V.C. Speer. V.W. Hays and D.V. Catron. 1958. Effect of 3-Nitro-4-Hydroxy- 
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176. Fowler, S.H. and G.L. Robertson. 1954. Some effects of source of protein and an antibi- 
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177. Francis, D.W. and C.S. Shaffner. 1956. An investigation of the morphological changes in 
young chickens and the reproductive performance of adult chickens fed fura/.olidone or 
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178. Franti, C.E., L.M. Julian and H.E. Adler. 1973. Antibiotic growth promotion: effects of 
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179. Frost, D.V. 1953. Considerations on the safety of arsanilic acid for use in poultry feeds. 
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180. Frost, D.V.. L.R. Overby and C.S. Henry. 1955. Arsenicals in feeds: Studies with arsanilic 
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64 



181. Gilliam, H.C. and J.R. Martin. 1975. Economic importance of antibiotics in feeds to pro- 
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182. Gilliam, Jr., H.C, J.R. Martin, W.G. Bursch and R.B. Smith. 1973. Economic conse- 
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184. Gordon, H.A. 1955. Morphologic characterization of germ-free life. Bull. N.Y. Acad. Med. 
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185a. Gordon, H.A. 1952. Studies on the growth effect of antibiotics in germ-free animals. 
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185b. Gordon, H.A., M. Wagner and B. Wostman. 1957. Studies on conventional and germ free 
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186. Gossett, P.O. and J. A. Miyat. 1964. A new antibiotic in treatment of swine dysentery. 
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187. Gouge, H.E., R.F. Elliott and O.K. Van Roekel. 1958. Effect of chlortetracycline on in- 
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188. Graber, G., M.C. Thomas, E.W. Lucas and M.J. Norvell. 1974. Influence of grain type on 
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189. Gray, Jr., R.C. and CD. Squiers. 1961. Antibiotic influence on reproduction in gilts. J. 
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190. Greene, D.E., R.C Eaton, W.C Schofield and H.L. Wilke. 1963. Observations on the oc- 
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191. Griffen, S.A., E.R. Lidvall and D.E. McKechnie. 1961. Thiofuradene, virginiamycin and 
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192. Groschke, A.C and R.J. Evans. 1950. Effect of antibiotics, synthetic vitamins, vitamin 
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193. Guenther, E. and CW. Carlson. 1964. Antibiotics in laying diets. Poultry Sci. 43:1324. 

194. Guenther, E. and CW. Carlson. 1965. Newer antibiotics in laying diets. Feed Age. 
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65 



195. Guenther, E. and C.W. Carlson. 1974. Some effects of copper sulfate, copper oxide and 
4-nitrophenylarsonic acid on aortic rupture and growth in turkeys. Poultry Sci. 53:1931 

196. Hale. O.M. and VV.C. McCorniick. 1975. Effect of cliiortetracycline on performance of 
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197. Hall, J.L., D.L. Harrison, L.L. Anderson, H. Parry and D.L. Mackintosh. 1963. Quality of 
meat from swine fed aureomycin or terramycin. J. Animal Sci. 22:571. 

198. Hammell, D.L. and H.N. Becker. 1976. Performance of swine fed antibiotics in the pre- 
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199. Hammell, D.L. and H.N. Becker. 1975. Performance of swine fed lincomycin. Anim. Sci. 
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200. Handlin, D.L. and J.C. McConnell. 1974. Feed additives for four-week-old pigs. Swine 
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201. Handlin. D.L. and M.E. Reid. 1977. Additives tor young pigs. Swine Field Day. Anim. Sci. 
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202. Hanke, H.E. and R.J. Meade. 1973. Influence of time of antibiotic and drug withdrawal 
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203. Hanke, H.E. and R.J. Meade. 1973. Influence of time of antibiotic and drug withdrawal 
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204. Hanson, L.E., L.E. Carpenter, W.J. Aunan and E.F. Ferrin. 1955. The use of arsanilic acid 
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205. Hanson, L.E.. E.F. Ferrin. P. A. Anderson and W.J. Aunan. 1955. Growth and carcass 
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206. Harper, J. A. and E.E. Babcock. 1953. Tlie effect of penicillin on early mortality and 
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207. Hash, J.H., M. Wishnick and P. A. Miller. 1964. On the mode of action of the tetracycline 
antibiotics in Staphylococcus aureus. J. Biol. Chem. 239:2070. 

208. Hauser, M.M., G.W. Anderson, W.F. Pepper and S.J. Slinger. 1956. Further evidence on 
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209. Hawbaker, J. A., F. Diaz, V.C. Speer. V.W. Hays and D.V. Catron. I960. The effect of 
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210. Hawbaker, J.A., V.C. Speer. V.W. Hays and D.V. Catron. 1961. Effect of copper sulfate 
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66 



21 la. Hays. V.W. 1^)?;^ SPF hogs: Do tlicy need antibiotics':' Hog Farm Management 10:12:30. 
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212a. Hays, V.W. 1969. Biological basis for the use of antibiotics in livestock production. Tlie 
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212b. Hays. V.W. and D.S. Baker. 1967. Unpublished research. 

2Lv Hays, V.W.. J.E. Drews and G.L. Cromwell. 1969. Effects of carbadox on the perform- 
ance of growing-finishing pigs. Univ. of Ky. Animal Sci. Res. Rep. p. 18. 

214. Hays. V.V/.. B.E. Langlois and G.L. Cromwell. 1973. Effect of virginiamycin on perform- 
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215. Hays, V.W., J.R. Overfield and G.L. Cromwell. 1969. Effects of aureomycin and copper 
sulfate on performance of growing-finishing pigs. Univ. of Ky. Animal Sci. Res. Rep. p. 17. 

216. Hays. V.W. and V.C. Speer. I960. Effect of spiramycin on growth and feed utilization of 
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217. Heeney, M.W. 1975. Comparison of mecadox. oleandomycin, ASP-250, aureomycin or 
tyian/sulfa, tylan-antibiotic feeding program for growing and finishing pigs. Research 
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218. Heeney, M.W. 1976. Effect of a predetermined level of chlortetracycline when combined 
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219. Heeney, M.W. 1976. Mecadox vs. ASP 250 and two levels of terramycin vs. 50 grams of 
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220a. Heeney, M.W. and R. Myers. 1976. Performance of growing-finishing pigs fed different 
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220b. Heeney. M.W. 1977. Private communication. Unpublished research. 

22 1 . Henricks, D.M., J.H. Conrad and W.M. Beeson. I960. Effects of antibiotics and combina- 
tions of antibiotics on growing-finishing swine. Purdue Swine Day. Mimeo AS 284. 

222. llenson, J.N., W.M. Beeson and T.W. Perry. 1954. Vitamin, amino acid and antibiotic sup- 
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223. Heth. D.A. and H.R. Bird. 19(i2. Growth response of chicks to antibiotics from 1950 to 
1961. Poultry Sci. 41:755. 

224. Ileuser. G.F. 1956. Feeding high levels of antibiotics to chickens. Poultry Sci. 35:81 . 

67 



225. Heuser, G.F. and L.C. Norris. 1952. Some results of feeding antibiotics to chickens. 
Poultry Sci. 31:857. 

226. Heywang. B.W. 1965. Effect of some antibiotics and furazolidone on performance of lay- 
ing chickens during hot weather. Poultry Sci. 44:1523. 

227. Heywang, B.W. 1952. The effect of antibiotics on the growth of white legliorn pullets. 
Poultry Sci. 31:581. 

228. Heywang, B.W. 1959. The effect of arsanUic acid and low levels of antibiotics on laying 
hens during hot weather. Poultry Sci. 38:854. 

229. Heywang, B.W. 1956. The effect of high levels of an antibiotic on laying chickens during 
hot weather. Poultry Sci. 35: 1 196. 

230. Heywang, B.W. 1957. The effect of higli levels of antibiotics on the growth of cliickens 
during hot weather. Poultry Sci. 36:335. 

231. Heywang, B.W. 1957. The relative effect of two higli levels of an antibiotic on laying 
chickens during hot weather. Pouhry Sci. 36:871. 

233. Hill, C.H. and J.W. Kelley. 1954. The effect of fish meal on the response of chicks to high 
levels of penicillin. Poultry Sci. 33:657. 

234. Hill, D.C., H.D. Branion and S.J. Slinger. 1952. Influence of environment on the growth 
response of chicks to penicillin. Poultry Sci. 31 :920. 

235. Hill, D.C., H.D. Branion, S.J. Slinger and G.W. Anderson. 1953. Iniluence of environment 
on the growth response of chicks to penicillin. Poultry Sci. 32:462. 

236. Hill, C.H., A.D. Keeling and J.W. Kelley. 1957. Studies on the effect of antibiotics on the 
intestinal weights of chicks. J. Nutr. 62:255. 

237. Hill, E.G. and N.L. Larson. 1955. Effect of chlortetracycline supplementation on growth 
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238. Hines, R.H. and G.L. Allee. 1971. Evaluation of antibacterial agents to improve growth 
and efficiency of weaned pigs. Report of Progress 181 Agric. Exp. Sta. Kansas State Univ. 

239. Hoefer. J.A., R.W. Luecke, F. Thorp, Jr. and R.J. Johnston. 1952. The effect of terra- 
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240. Hogue, D.E., R.G. Warner, J.K. Loosli and C.H. Grippin. 1957. Comparison of antibiotics 
for dairy calves on two levels of milk feeding. J. Dairy Sci. 40: 1072. 

241. Holder, D.P. and T.W. Sullivan. 1972. The effect of terramycin, penicillin, bacitracin and 
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242. Hollis, G.R. 1970. A study of various feed additives in a pig starter program. Mimeo Ser. 
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68 



243. Holmquist, C.E., R.A. Nelson and C.W. Carlson. 1973. Neo-terramycin and egg produc- 
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244. Holmquist, C.E., R.A. Nelson and C.W. Carlson. 1973. Some effects of low protein grower 
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245. Homb, T. 1961. Norwegian experiments on antibiotic supplementation of bacon pigs. 
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246. Horvath, D.J. and G.W. Vander Noot. 1954. Effect of 3 levels of a new antibiotic, tetra- 
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247. Huck, D.W., J.A. Coalson and A.J. Clawson. 1977. Private communication. Unpublished 
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248. Hufftanen, C.N. and J.M. Pensack. 1965. The role of Streptococcus faecales in the anti- 
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249. Hvidsten, H. 1962. Effect of low and high levels of antibiotics in successive experiments 
with bacon pigs in the same herd. Tidsskrift for Det Norske Landbruk 69:14. 

250. Hvidsten, H. and T. Homb. 1961. The effect of supplementary terramycin and aureomy- 
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251. Isgrigg, W.N. and J.H. Trammell. 1975. The effect of zinc bacitracin on broiler perform- 
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252. Isgrigg, W.N. 1977. Private communication. Unpublished research. 

253. Jacobs, R.L., J.F. Elam, G.W. Anderson, L.L. Gee, J. Fowler and J.R. Couch. 1953. Fur- 
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254. Jensen, A.H. 1977. Unpublished Experiment. Private Communication. 

255. Jensen, A.H. 1974. Unpublished Experiment. Private Communication. 

256. Jensen, A.H. 1973. Unpublished Experiment. Private Communication. 

257. Jensen, A.H. and D.E. Becker. 1961 . Comparison of different antibiotics and an arsenical 
for pigs weaned at two to four weeks of age. Illinois Swine Growers Day. Mimeo AS-550. 

258. Johansson, K.R. and W.B. Sarles. 1949. Some considerations of the biological importance 
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259. Johnson, D.D.. R.F. Elliot, J.J. Drain and R.G. Brown. 1961 . Chlortetracycline-sulfameth- 
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69 



260. Johnson. D.D.. R.F. Elhol, J.J. Drain and R.G. Brown. 1964. The vakie of chlortetra- 
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261. Johnson, H.L. 1952. Providing vitamin Bj 2- antibiotic and unknown growth factor activi- 
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262a. Jones, J.R. and W.G. Pond. 1963. Effect of the addition of lysine and virginiamycin to 
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262b. Jt)rdan, C.E. 1967. Private communication. Unpublished research. 

263. Jordan, C.E. and W.P. Waitt. 1963. The effect of tyU)sin when fed to sows during farrow- 
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264. Jordan, C.E., W.P. Waitt and T.M. Means. 1961. Effects of new antibiotic, tylosin, on 
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265. Jordan. C.E., W.P. Waitt, T.M. Means, F.R. Carter and C.E. Redman. 1961 . Comparison 
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266. Jowsey, J.R., R.M. Blakely and fl.l. MacGregor. 1961. Growth response of turkey poults 
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267. Jukes, H.G., D.C. Hill and H.D. Branion. 1956. Effect of antibiotic on rate of passage of 
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268. Jukes, H.G., D.C. Hill and H.D. Branion. 1956. Effect of feeding antibiotics on the in- 
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269. Jukes, H.G., D.C. Hill and H.D. Branion. 1957. Effect of penicillin on the carcass compo- 
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270. Jukes, T.H., E.L.R. Stokstad, R.R. Taylor, T.J. Cunha, H.M. Edwards and B.G. Meadows. 
1950. Growth promoting effect of aureomycin on pigs. Arch. Biochem. 26:324. 

271. Jukes, T.H. and W.L.Williams. 1953. Nutritional effects of antibiotics. Pharm. Rev. 5:381. 

272. Kellog, T.F., V.W. Hays, D.V. Catron, L.Y. Quinn and V.C. Speer. 1966. Effect of dietary 
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273a. Kellog, T.F., V.W. Hays, D.V. Catron, L.Y. Quinn and V.C. Speer. 1964. Effect of level and 
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273b. Kiser, J.S. Private communication. Llnpublished research. 

274. Kling, II. F., R.J. Grant, M.W. Moeller, R.ll. Harms, B.L. Damron, C.L. Quarles, B.C. Dil- 
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70 



275. KJing, H.F., M.W. Moeller, B.L. Damron, R.H. Harms, C.L. Quarles, L.M. Potter, W.L. 
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276. Koch, B.A. and R.H. Hines. 1970. Corn or sorghum grain in growing-finishing rations 
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277. Koh, F.K., N.L. Tai, T.P. Yeh, Y.S. Shih, J.F. Wu, H.T. Yen, H.N. Lu and H.C. Chow. 
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278. Kornegay, E.T., K.G. Libke and D.F.Watson. 1969. Evaluation of new antibiotic-sulfa 
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279. Kornegay, E.T., H.R. Thomas and J.H. Carter. 1972. Rotation of feed additives in swine 
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280. Kornegay, E.T., H.R. Thomas and C.Y. Kramer. 1975. Effect on subsequent feed lot per- 
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281 Kornegay, E.T., H.R. Thomas and C.Y. Kramer. 1975. Rotating or withdrawing dietary 
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282. Kratzer, F.H. 1952. The effect of liver concentrate and aureomycin upon the growth of 
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283. Kratzer, F.H. 1952. Vitamin B12 and antibiotics in the diet of turkey poults from hens 
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284. Krider, J.L., R.G. Jones, R.B. Harrington, L.B. Underwood and E.V. Morse. 1976. Che- 
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285. Krider, J.L., M.P. Plumlee, J.C. Russett, R.B. Harrington and L.B. Underwood. 1975. 
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286. Krueger, W.F., M.A. Wahid and J.H. Quisenberry. 1966. The effect of sulfaquinoxaline 
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287. Krug, J.L. 1976. Effects of length of lactation and chlortetracycline on reproductive per- 
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288. Krug, J.L., V.W. Hays, G.L. Cromwell, R.H. Dutt and D.D. Kratzer. 1975. Effects of 
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71 



289. Lasley, J.F., L.F. Tribble and A.G. Hogan. 1954. Value of antibiotics in swine rations. 
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290. Lehrer, Jr., VV.P., E.R. Pharris. W.R. Harvey and T.B. Keith. 1953. Grow^th effects of some 
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291. Leibbrandt, V.D. and H.N. Becker. 1977. Feed antimicrobials for growing-tlnishing swine. 
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292. Lev, M., C.A.E. Briggs and M.E. Coates. 1957. The gut flora of the chick. 3. Differences in 
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293. Lev, M. and M. Forbes. 1959. Growth response to dietary penicillin of germ-free chicks 
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294. Libai, G.W., S.L. Robins and R.C. Wahlstrom. 1975. Chlortetracycline and arsanilic acid 
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295. Libby. D.A., R.J. Evans, S.L. Bandemer and P.J. Schaible. 1955. Effect of long-time feed- 
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296. Libby, D.A. and P.J. Schaible. 1955. Observations on growth response to antibiotics and 
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297. Lillie, R.J. and H.R. Bird. 1952. Effect of antibiotic supplements upon hatchability and 
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298. Lillie, R.J., L.T. Frobish, N.C. Steele and G. Graber. 1977. Effect of dietary copper and 
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299. Lillie, R.J. and J.R. Sizemore. 1954. Effect of antibiotics on egg production of New 
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300. Lillie, R.J.. J.R. Sizemore and H.R. Bird. 1953. Environment and stimulation of growth 
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301. Lillie, R.J., J.R. Sizemore and C.A. Denton. 1957. Effect of an arsenical, fat and anti- 
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302. Lima, F.R., T.S. Stalily and G.L. Cromwell. 1977. Combinations and single additions of 
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303. Lindblad, G.S., S.J. Slinger and L Motzok. 1954. Effect of aureomycin on the calcium 
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304. Lucas, I. A.M. 1957. Antibiotic supplements in rations for pigs. Vet. Rec. 69:233. 

72 



305. Luckey. T.D., H.A. Gordon. M. Wagner and J. A. Reyniers. 1956. Growth of germ-free 
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306. Luecke. R.W..F. Thorp. Jr.. Fl.W. Newland and W.N. McMillen. 1951. The growth promo- 
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307. MacAuliffe, T. and J. McGinnis. 1971 . EtTecl of antibiotic supplements to diets contain- 
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308. MacAuliffe, T., A. Pietraszek and J. McGinnis. 1976. The effect of grain component of 
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309. MacGrogor. 11.1., R.M. Blakely and R.W. Anderson. 1954. Antibiotics in the diet of turkey 
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310. MacGregor. 11. 1.. R.M. Blakely and R.W. Anderson. 1952. Growth response o\' turkey 
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311. Machlin. L.J., C.A. Denton. W.L. Kellogg and H.R. Bird. 1951. Effect of dietary antibiotic 
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312. Maddock, 11. 1977. Private cimimunication. Unpublished research. 

313. Mahan, D.C.and ll.W. Newland. 1976. Short term elTects of the addition of oats, bacterial 
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314. March. B.E. and J. Biel\'. 1967. A reassessment o\' the mode of action o\' the growth 
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315. March, B. and J. Biely. 1952. The effect of feeding aureomycin i)n the bacterial content of 
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316. March, B.E.. A.y\. Kinwande and R. Soong. 1972. The effect of feeding antibiotics lor dif- 
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317. March, B.E., T. Smith and M. Sadic]. 1975. Factors affeclnig estimates o\ melaboli/able 
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318. Marusich. W.L., E. Ogrin/. M. Brand and M. Mitri)vic. 19(i9. Safety and compalibilitv o\' 
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319. Marusich. W.L.. E.F. Ogrin/, P.R. Bnnvn and M. Milro\ic. 1973. Comparative efficacy o\' 
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320. Marusich, \V.L.. E.I-. Ogrin/. N. Comerlengii and M. Milrovic. 1977. Effect of diet on the 

73 



performance of broiler chicks fed lasalocid in combination with growth promotants. 
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321. Marusich, W.L., E.F. Ogrinz and M. Mitrovic. 1974. A new antibiotic, X-5 108, for improv- 
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322. Maxey, B.W. and R.K. Page. 1977. Efficacy of lincomycin feed medication for the con- 
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323. Mayrose, V.B., V.C. Speer, V.W. Hays and J.T. McCall. 1964. Effect of an antibiotic and 
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324. Mayrose, V.B., V.C. Speer, V.W. Hays and J.T. McCall. 1964. Effect of an antibiotic(tylo- 
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325. McCartney, M.G. and E.C. Naber. 1960. Influence of furazolidone on the reproductive 
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326. McDonald, M.W. 1955. A failure of chickens to respond to arsanilic acid. Poultry Sci. 
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327. McGinnis, J. 1951. The effect of antibiotics on the nutritional requirements of turkeys 
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328. McGinnis, J., L.H. Merrill, R.E. Fry and L.S. Jensen. 1958. Use-history of antibiotics as 
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329. McGinnis, J. and J.R. Stern. 1953. Effect of the feed pelleting process on growth response 
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330. McGinnis. J.. J.R. Stern. R.A. Wilcox and J.S. Carver. 1951. The effect of different anti- 
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331. McKigney, J. I., H.D. Wallace and T.J. Cunha. 1955. The influence of chlortetracycline 
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332. Meade, R.J. and R.M. Forbes. 1956. The influence of chlortetracycline and vitamin B|2 
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333. Meade, R.J. and H.E. Hanke. 1971. Influence of antibacterial preparations on rate and 
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335. Meade, R.J., J.W. Rust and H.E. Hanke. 1972. Influence of flavomycin and tylosin supple- 
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74 



336. Melliere, A.L. 1977. Private communication. Unpublished research. 

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338. Melliere, A.L., H. Brown and R.P. Rathmacher. 1973. Finishing swine performance and 
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339. Menge, H. 1973. Lack of growth response of eight-week-old broilers to certain antibiotics. 
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340. Menge, H. and R.J. Lillie. 1960. Ineffectiveness of antibiotic combination on response of 
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341. Mente, G. Private communication. Unpublished research. 

342. Messersmith, R.E., D.D. Johnson, R.F. Elliot and J.J. Drain. 1966. Value of chlortetracy- 
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345. Miller, E.R., J.P. Hitchock, D.E. Orr and D.E. Ullrey. 1972. Virginiamycin for growing- 
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346. Miller, E.R. and E.C. Miller. 1975. High level antibiotics in a swine waste recycling sys- 
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347. Miller, H.W. and C.E. Barnhart. 1961. Growth stimulants and antibacterial agents. J. 
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348. Miller, H.W., C.E. Barnhart and T.W. Cathey. 1961 . Antibiotics as additives in early wean- 
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349. Miller, H.W., C.E. Barnhart and T.W. Cathey. 1961. Feed additives for growing-finishing 
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352. Mitrovic, M., E.G. Schildknecht and W.L. Marusich. 1975. Comparative activity and com- 
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353. Miyat, J. A. and F.O. Gossett. A new antibiotic in treatment of swine dysentery. Vet. 
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75 



354. Mueller. M.W., C.L. Qiiaiies, H.F. Kling. B.C. Dilworth, E.J. Day. B.L. Damron and R.H. 
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355. Moeller. M.W., P.E. Waibel, C.L. Quarles, H.F. Kling, P.W. Waldroup, L.M. Potter and 
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363. Moran, Jr., E.T. and J. McGinnis. 1965. The effect of cereal grain and energy level of the 
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364. Morehouse, N.F. 1949. Accelerated growth in chickens and turkeys produced by 3-nitro- 
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365. Morehouse, N.F. 1954. The effect of 3-nitro-4-hydroxyphenylarsonic acid on reproduc- 
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366. Morehouse, N.F. and O.J. May field. 1946. The effect of some aryl arsonic acids on experi- 
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76 



.^dS. Morrison. W.D., A.W. Tremcrc and J.F. Standish. 1974. Respon.se of broiler chicks to 
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371. Myers, D.J. and V.C. Speer. 1973. Effect of an antibiotic and flushing on performance of 
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372. Myers, D.J. and V.C. Speer. 1972. Effects of an antibiotic and Hushing on sow perform- 
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373. Nakaue, H.S., J.M. Thomas and B.L. Reid. 1967. Comparison of EDTA, terephthalic acid, 
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374. Natz, D. 1973. Report measures economic gains from feed antibiotics. Feedstuffs 45:2:73. 

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377. Nelson, F.E., L.S. Jensen and J. McGinnis. I960. Effect of antibiotics on growth rate, in- 
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379. Nelson, F.E., L.S. Jensen and J. McGinnis. 1963. Studies on the stinnilation of growth by 
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380. Nelson, L.F. 1977. Additives improve performance in swine rations. Feedlot News. Sept. 
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381. Newman, C.W. and D.O. Elliot. 1970. Antibit)tic and chemotherapeutic combinations for 
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383. Nivas, S.C, M.L. Sunde and H.R. Bird. 1967. Erythromycin thiticyanate and the perform- 
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77 



384. Nivas. S.C., M.D. York and B.S. Pomeroy. 1^76. HtTects of different levels of chlortetra- 
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385. Noland, P.R. l*-)77. Private communication. Unpublished research. 

386. Noland, P.R. and R.W. McC.hee. |Q73. Use of antibiotics in swine rations. Ark. Farm Re- 
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387. Obibuaku, L.O., M.L. Sunde and H.R. Bird. 1966. The effect of furadroxyl on the per- 
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388. Oleson, J.J., B.L. Hatchings and A.R. Whitehill. 1950. The effect of feeding aureomycin 
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389. O'Neal, R.M. and J.E. Savage. 1959. A comparison of continuous and intermittent feeding 
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390. Orr, D.E., L.F. Tribble, D.M. Hellman and J. Allen. 1977. Etlectiveness of selected anti- 
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391. Overfield, J.R., C.E. Barnhart and S.J. Lowry. 1960. Value of some nitro-furans as feed 
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393. Patrick, H. 1952. The effects of homocystine, methionine, vitamin B12 ^fiJ antibiotics in 
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394. Patrick, H. 1951. Vitamin B12 :nid antibiotics in turkey poult nutrition. Poultry Sci. 
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395. Pelura, 111, J., J.L. Krider and T.R. Cliiic. 1977. Effects of virginiamycin in creep and 
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397. Peo, Jr., E.R. 1962. Effectiveness of antibiotic supplements. Nebraska Swine Day Report 
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398. Peo, Jr., E.R. 1977. Private comniunicaticMi. Unpublished research. 

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78 



400. Pepper, W.F., S.J. Slinger and J.E. Bergey. 1954. Effect of 3-nitro-4-hydroxyphenylarsonic 
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401. Pepper, W.F., S.J. Slinger and I. Motzok. 1952. Effect of aureomycin on the manganese 
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404. Petersen, C.F. and C.E.Lampman. 1952. Value of antibiotics in rations for egg production 
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405. Petersen, C.F., E.A. Sauter, D.H. Conrad and G.J. Anderson. 1958. The influence of pen-, 
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406. Petersen, C.F., A.C. Wiese, R.V. Dahlstrom and C.E. Wampman. 1952. Influence of vita- 
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407. Peterson, E.H. 1952. Terramycin reduces early poult mortality. Poultry Sci. 31 :898. 

408. Pettigrew, J. 1977. Private communication. Unpublished research. 

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41 1. Potter, L.M. 1972. Effects of erythromycin, fermacto-500, herring fish meal and taurine 
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412. Potter, L.M. 1971. Future use of antibiotics in poultry feeds. Feedstuffs 43:34:14. 

413. Potter, L.M. 1977. Private communication. Unpublished research. 

414. Potter, L.M., L.D. Matterson, J.J. Tlustohowicz and E.P. Singsen. 1962. The relative 
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415. Potter, L.M., F.A. Ryan, L.D. Matterson, E.P. Singsen and J. Tlustohowicz. 1963. Effects 
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416. Potter. L.M. and J.R. Shelton. 1976. Dried whey product, menhaden fish meal, methio- 
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79 



417. Potter, L.M.. J.R. Shelton and M. Kelly. \^^7\. Ht'i'ects of zinc bucitiacin. dried bakery- 
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419. Potter, L.M., J.R. Shelton and L.G. Melton. 1974. Zinc bacitracin and added fal in diets 
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420. Potter, L.M.. J.R. Shelton and E.E. Pierson. 1977. Menhaden fish meal, dried tlsh solubles, 
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421. Prasad, S.,W.T. Hairr and J.T. Dallas. 1972. The effects of moneiutnncin supplementation 
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423. Ramage, D.R., C.E. Barnhart and C.H. Chancy and T.W Cathey. 1962. A comparison of 
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425. Ramage, D.R.,-C.E. Barnhart, C.H. Chaney and T.W. Cathey. 1962. Further studies with 
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428. Raper, K.B. 1952. A decade of antibiotics in America. Mycologia 44:1 . 

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430. Rolf. M. 1977. Private ct)mmunication. Unpublished research. 

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80 



433b. RusotT. L.L.. F.I. Landogora and H.H. Hester. 1954. Effect of aureomycin on certain 
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435. Rust, J.W. and R.J. Meade. 1973. Influence of omission of drug from the starter diet and 
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440. Satava, M. 1967. Antibiotics of tetracycline series in chick fattening - 1st research stage. 
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441. Sauer, N.G., L.S. Jensen and J.V. Shutze. 1969. The influence of furazolidone on egg 
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442. Sa.xena, H.C., L.R. Berg and J. McGinnis. 1952. Factors affecting the growth response of 
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443. Saxena, H.C., E.G. Blaylock, J.S. Carver and J. McGinnis. 1953. Factors affecting the 
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447. Schneider, B.H., G.R. Spencer and M.E. Ensminger. 1955. Antibiotic feeding for prophy- 
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449. Scott, H.M. 1962. The effect of a non-specific infection on chick growth. Proc. III. Nutr. 
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450. Scott, H.M. and W.A. Glista. 1950. The effect of aureomycin and arsonic acid on chick 
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451. Scott, HJvl., E.A. Goffi and W.A. GHsta. 1952. The protein requirement of the chick as 
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452. Scott, H.M., B.C. Johnson and E.A. Goffi. 1952. Effect of surface active agents on chick 
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453. Scott, M.L. and L.S. Jensen. 1952. The effect of antibiotics upon the requirement of 
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82 



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83 



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